Abstract
The evolution of genetic mechanisms for host immune evasion and anti-malarial resistance has enabled the Plasmodium falciparum malaria parasite to inflict high morbidity and mortality on human populations. Most studies of P. falciparum genetic diversity have focused on single-nucleotide polymorphisms (SNPs), assisting the identification of drug resistance-associated loci such as the chloroquine related crt and sulfadoxine-pyrimethamine related dhfr. Whilst larger structural variants are known to impact adaptation, for example, mdr1 duplications with anti-malarial resistance, no large-scale, genome-wide study on clinical isolates has been undertaken using whole genome sequencing data. By applying a structural variant detection pipeline across whole genome sequence data from 2,855 clinical isolates in 21 malaria-endemic countries, we identified >70,000 specific deletions and >600 duplications. Most structural variants are rare (48.5% of deletions and 94.7% of duplications are found in single isolates) with 2.4% of deletions and 0.2% of duplications found in >5% of global isolates. A subset of variants was present at high frequency in drug-resistance related genes including mdr1, the gch1 promoter region, and a putative novel duplication of crt. Regional-specific variants were identified, and a companion visualisation tool has been developed to assist web-based investigation of these polymorphisms by the wider scientific community.
Highlights
Plasmodium falciparum malaria imposes a heavy morbidity and mortality burden, with an estimated 216 million new cases and 446,000 deaths in 2016 alone, with ~90% of the burden in sub-Saharan Africa[1]
Using a structural variant (SV) discovery pipeline based primarily upon DELLY13, we identified more than 1 million putative variants deletions and duplications relative to the 3D7 reference genome, across robust regions (~83%; excluding regions that were highly variable or within 100 kbp of a chromosome end) of the P. falciparum genome
Given that SVs can have a significant impact on gene expression and anti-malarial resistance, we focused an analysis on the identification of novel structural variants in candidate genes
Summary
Plasmodium falciparum malaria imposes a heavy morbidity and mortality burden, with an estimated 216 million new cases and 446,000 deaths in 2016 alone, with ~90% of the burden in sub-Saharan Africa[1]. We identified a novel promoter duplication for gch[1] at near-fixation in a Malawi population[5], which is distinct from the whole gene duplication observed in Southeast Asia known to contribute to sulfadoxine-pyrimethamine (SP) resistance Such regional genetic variation may arise from differences in drug regimens, mosquito vectors, and host immunity, but is poorly understood. Given their importance, a genome-wide structural variant map for P. falciparum with country and regional resolution should provide insights with which to better understand the impacts of treatment regimes, assess changes in parasite diversity, and inform the roll-out of anti-malarial drugs and other control initiatives. We confirm specific variants using several alternative approaches, including the analysis of PacBio long-read data of P. falciparum laboratory strains
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