Abstract
Genes underlying important phenotypic differences between Plasmodium species, the causative agents of malaria, are frequently found in only a subset of species and cluster at dynamically evolving subtelomeric regions of chromosomes. We hypothesized that chromosome-internal regions of Plasmodium genomes harbour additional species subset-specific genes that underlie differences in human pathogenicity, human-to-human transmissibility, and human virulence. We combined sequence similarity searches with synteny block analyses to identify species subset-specific genes in chromosome-internal regions of six published Plasmodium genomes, including Plasmodium falciparum, Plasmodium vivax, Plasmodium knowlesi, Plasmodium yoelii, Plasmodium berghei, and Plasmodium chabaudi. To improve comparative analysis, we first revised incorrectly annotated gene models using homology-based gene finders and examined putative subset-specific genes within syntenic contexts. Confirmed subset-specific genes were then analyzed for their role in biological pathways and examined for molecular functions using publicly available databases. We identified 16 genes that are well conserved in the three primate parasites but not found in rodent parasites, including three key enzymes of the thiamine (vitamin B1) biosynthesis pathway. Thirteen genes were found to be present in both human parasites but absent in the monkey parasite P. knowlesi, including genes specifically upregulated in sporozoites or gametocytes that could be linked to parasite transmission success between humans. Furthermore, we propose 15 chromosome-internal P. falciparum-specific genes as new candidate genes underlying increased human virulence and detected a currently uncharacterized cluster of P. vivax-specific genes on chromosome 6 likely involved in erythrocyte invasion. In conclusion, Plasmodium species harbour many chromosome-internal differences in the form of protein-coding genes, some of which are potentially linked to human disease and thus promising leads for future laboratory research.
Highlights
With the availability of complete genome sequences of both human and non-human Plasmodium parasites, the causative agents of malaria, it is possible to use comparative genomics as a tool to look for genes that are present in some but not all Plasmodium species
We performed a comprehensive computational comparison of the published genomes of six Plasmodium species, including two human (P. falciparum and P. vivax), one monkey (P. knowlesi), and three rodent malaria parasites (P. berghei, P. yoelii, and P. chabaudi). This comparison revealed many species subset-specific genes that are potentially linked to human pathogenicity, human-tohuman transmissibility, and human virulence
Gene model improvement in P. vivax and P. knowlesi Six published Plasmodium genomes sequenced to high coverage were selected for comparison, including the two clinically most important human parasites (P. falciparum and P. vivax), one monkey parasite (P. knowlesi), and three rodent parasites (P. chabaudi, P. berghei, and P. yoelii) (Figure S1)
Summary
Malaria is an infectious disease caused by single-celled intracellular eukaryotic parasites of the genus Plasmodium that are transmitted by mosquitoes. Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae and Plasmodium ovale, are traditionally recognized as human parasites. Other Plasmodium species are important model parasites in malaria research, including the primate malaria model Plasmodium knowlesi, which parasitizes macaque monkeys in the wild, as well as the three rodent malaria parasites Plasmodium berghei, Plasmodium yoelii, and Plasmodium chabaudi, which are natural parasites of thicket rats in central Africa. Plasmodium species that naturally infect humans, monkeys, and rodents differ in their ability to cause human disease. The macaque monkey parasite P. knowlesi differs from the four human parasites in that it is not endemic in larger parts of the human population despite its known ability to infect humans under natural conditions [4]. P. vivax, the major cause of human malaria outside Africa, rarely kills, cases
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