PlasmoView: a web-based resource to visualise global Plasmodium falciparum genomic variation

Abstract

Malaria is a global public health challenge, with drug resistance a major barrier to disease control and elimination. To meet the urgent need for better treatments and vaccines, a deeper knowledge of Plasmodium biology and malaria epidemiology is required. An improved understanding of the genomic variation of malaria parasites, especially the most virulent Plasmodium falciparum (Pf) species, has the potential to yield new insights in these areas. High-throughput sequencing and genotyping is generating large amounts of genomic data across multiple parasite populations. The resulting ability to identify informative variants, particularly single-nucleotide polymorphisms (SNPs), will lead to the discovery of intra- and inter-population differences and thus enable the development of genetic barcodes for diagnostic assays and clinical studies. Knowledge of genetic variability underlying drug resistance and other differential phenotypes will also facilitate the identification of novel mutations and contribute to surveillance and stratified medicine applications. The PlasmoView interactive web-browsing tool enables the research community to visualise genomic variation and annotation (eg, biological function) in a geographic setting. The first release contains over 600,000 high-quality SNPs in 631 Pf isolates from laboratory strains and four malaria-endemic regions (West Africa, East Africa, Southeast Asia and Oceania).

Keywords: Plasmodium falciparum; drug resistance; genomics; malaria; vaccine targets; visualization.

Figure 1.

Global mutations in the Pf chloroquine resistance transporter gene (PfCRT). The 61 SNPs (18 non-synonymous) identified in PfCRT (Chromosome 7, PF3D7_0709000) are shown. Some markers (eg, Q271E) show evidence that they have gone to fixation in SEA (blue on the left axis) and are common throughout the rest of the world (WAF: green; EAF: yellow; OCE: purple on the left axis). Six known drug resistance markers are shown, as well as 3 common SNPs located in intronic regions (IT).

Figure 2.

Global distribution of the resistance-conferring PfCRT mutation K76T. The global prevalence of the K76T mutation (Chromosome 7, position 403 615) can be seen with the mutation fixed or close to fixed in most countries. Parasites may have reverted back to the wildtype allele, due to the complete withdrawal of chloroquine from some countries (eg, in East Africa, yellow on the left axis). The LAB Pf strains (laboratory-adapted and imported Pf strains) are located over the South Atlantic. Information on each bar chart is available by holding the cursor over it.

Figure 3.

Pf chromosome 13, 1770 kb to 1820 kb. Cheeseman et al [8] described this region as being potentially important to the evolution of artemisinin-resistant Pf parasites in Southeast Asia. Of the 1355 SNPs in this 50-kb region, more than 20 exhibit high regional specificity (predominantly in SEA with high F_ST (>0.1) and low MAF (<30%)) and at least 10 may have spread or are currently spreading to other regions (high MAF and low F_ST). Gene Pf3D7_1344700 (see Supplementary Figure 2D) contains an example of both: a SNP with high regional specificity (position 1 793 121, labelled as SNP 1 in [8], Supplementary Figure 2E) and one moving towards global fixation (position 1 794 574).

Figure 4.

PfRH5 vaccine candidate in chromosome 4. The Pf Reticulocyte Binding Protein Homologue 5 (PfRH5, PF3D7_0424100) gene is considered a promising vaccine candidate, as it seems to be essential for blood-stage parasite invasion of red blood cells [20]. The locus contains 28 SNPs, including 5 non-synonymous mutations with MAF >10% (I410M, S197Y, H148D, Y147H [19] and K419N [20]).

Figure 5.

AMA1 vaccine candidate in chromosome 11. The apical membrane antigen 1 gene (AMA1, Chromosome 11, PF3D7_1133400) has long been recognised as a vaccine candidate and is currently being evaluated in clinical trials [22]. The high number of SNPs with intermediate MAF and low F_ST indicate that this locus is under balancing selection.

Figure 6.

Mitochondrial genome. The Pf mitochondrion is a small, uniparentally inherited organelle and its DNA (6 kb) is used for investigating Pf evolution and migration [23, 24, 26]. Six SNPs exhibit population differentiation (F_ST > 0.05; mt74, mt772, mt1692, mt1776, mt2383 and mt2641) including three common alleles (MAF > 5%; mt772, mt1692 and mt1776) used to support an African origin for the species [24, 26].