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Abstract

Malaria elimination strategies require surveillance of the parasite population for genetic changes that demand a public health response, such as new forms of drug resistance. Here we describe methods for the large-scale analysis of genetic variation in Plasmodium falciparum by deep sequencing of parasite DNA obtained from the blood of patients with malaria, either directly or after short-term culture. Analysis of 86,158 exonic single nucleotide polymorphisms that passed genotyping quality control in 227 samples from Africa, Asia and Oceania provides genome-wide estimates of allele frequency distribution, population structure and linkage disequilibrium. By comparing the genetic diversity of individual infections with that of the local parasite population, we derive a metric of within-host diversity that is related to the level of inbreeding in the population. An open-access web application has been established for the exploration of regional differences in allele frequency and of highly differentiated loci in the P. falciparum genome.

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Figures

Figure 1
Figure 1
(a) Minor allele frequency distribution of 86k SNPs set in samples from different continents (AFR, SEA and PNG). Vertical axis shows the number of SNPs in each category of allele frequency. Supplementary Figure S7 shows the data corrected for sample size (b) Considers SNPs that are private to either AFR, SEA or PNG, showing the ratio of nonsynonymous to synonymous substitutions (vertical axis) as a function of derived allele frequency (horizontal axis)
Figure 1
Figure 1
(a) Minor allele frequency distribution of 86k SNPs set in samples from different continents (AFR, SEA and PNG). Vertical axis shows the number of SNPs in each category of allele frequency. Supplementary Figure S7 shows the data corrected for sample size (b) Considers SNPs that are private to either AFR, SEA or PNG, showing the ratio of nonsynonymous to synonymous substitutions (vertical axis) as a function of derived allele frequency (horizontal axis)
Figure 2
Figure 2
Representations of a pairwise distance matrix between the 227 samples analyzed. (a) Principal components analysis (b) Unrooted neighbour-joining tree. Leaf branches are coloured according to the country of origin of the sample.
Figure 2
Figure 2
Representations of a pairwise distance matrix between the 227 samples analyzed. (a) Principal components analysis (b) Unrooted neighbour-joining tree. Leaf branches are coloured according to the country of origin of the sample.
Figure 3
Figure 3
(a) Relationship between heterozygosity in the local parasite population (HS, horizontal axis) and within-host heterozygosity (HW, vertical axis) for all samples in the WAF population. Each line represents a different sample, whose within-host heterozygosity values were averages across all SNPs, categorised according to their heterozygosity in the local parasite population. Separate plots for each population are shown in Supplementary Figure S17). (b) Boxplot showing the distribution of FWS estimates in samples from each of the four populations.
Figure 3
Figure 3
(a) Relationship between heterozygosity in the local parasite population (HS, horizontal axis) and within-host heterozygosity (HW, vertical axis) for all samples in the WAF population. Each line represents a different sample, whose within-host heterozygosity values were averages across all SNPs, categorised according to their heterozygosity in the local parasite population. Separate plots for each population are shown in Supplementary Figure S17). (b) Boxplot showing the distribution of FWS estimates in samples from each of the four populations.

Comment in

References

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