Comparative genomics of the neglected human malaria parasite Plasmodium vivax

Abstract

The human malaria parasite Plasmodium vivax is responsible for 25-40% of the approximately 515 million annual cases of malaria worldwide. Although seldom fatal, the parasite elicits severe and incapacitating clinical symptoms and often causes relapses months after a primary infection has cleared. Despite its importance as a major human pathogen, P. vivax is little studied because it cannot be propagated continuously in the laboratory except in non-human primates. We sequenced the genome of P. vivax to shed light on its distinctive biological features, and as a means to drive development of new drugs and vaccines. Here we describe the synteny and isochore structure of P. vivax chromosomes, and show that the parasite resembles other malaria parasites in gene content and metabolic potential, but possesses novel gene families and potential alternative invasion pathways not recognized previously. Completion of the P. vivax genome provides the scientific community with a valuable resource that can be used to advance investigation into this neglected species.

Figure 1. Predicted erythrocyte invasion pathways and dominant ligands of Plasmodium species

RBL and DBL invasion families predicted from several Plasmodium proteomes are shown above a Plasmodium merozoite colliding and reorientating on the red blood cell surface. Species-specific RBL families interact with an array of species-specific DBL proteins that utilize both alternative (crossed arrows) and fixed (straight arrows) pathways with known or predicted receptors on the surface of erythrocytes. Blocking these receptor-ligand interactions offers a potential mechanism to prevent clinical malaria. GPA/B/C: P. falciparum glycophorin A/B/C receptors; “X”, “Y”: predicted receptors; RH SA+/-: Rhesus sialic acid dependent (+) and independent (-) pathways; DARC: Duffy antigen receptor for chemokines dependent (+) and independent (-) pathways; * presence of this pathway is controversial.

Figure 2. VIR protein motifs and organization

The structure of an archetypal vir gene is shown at top, followed by VIR subfamily motifs arranged from the N-terminus (left) to the C-terminus (right). Consensus motif sequences numbered in decreasing order of statistical significance are shown color coded below the figure. Motif 2: transmembrane (TM) domain; motif 3: PEXEL/VSP-like motif; all remaining motifs are predicted exposed globular domains. The overall organization and order of the motifs is maintained, with the central core motifs 9, 1, 3, 6 and 10 followed by C-terminus motifs 7, 2, 4, 8 and 5 embedded in a variant-sized portion of the molecule. Motifs are listed in the Supplementary Information.

Plate 1. Synteny maps showing the comparative organization of Plasmodium chromosomes

Putative orthologs were computed between P. falciparum (Pf), P. vivax (Pv), P. knowlesi (Pk) and P. y. yoelii (Py) proteomes and used to define blocks of synteny (shaded regions) between Py - Pk, Pk - Pv, and Pv – Pf chromosomes. Genes on contigs that could not be assigned to chromosomes are not shown (see Supplementary Information). The composite rodent malaria parasite (cRMP) chromosomes generated in Ref. are shown. Plots below the Pv chromosomes display the following: MS, the position of polymorphic microsatellites; G+C-skew, the base composition within each strand; %G+C, the percent G+C; and for Pv-Pk, two evolutionary parameters d_S and ω. Inset: Distribution of selective constraints (ω) for Biological Process (A), Molecular Function (B) and Cellular Component (C) Gene Ontology classifications. Selective constraint is also shown for several motifs (D): proteins containing predicted transmembrane domains (TMM) and/or signal peptides (SP); GPI-anchored proteins; proteins predicted to be exported from the cell (exportome). Each grey box represents the interquartile range (IQR), which contains the sample’s 25% to 75% range (quartiles Q1 to Q3, respectively), and the median is indicated (black tick within IQR). Horizontal tick marks outside IQR show the range of all elements within Q1-1.5*IQR and Q3+1.5*IQR (~99.3% interval of a normal distribution).