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. 2019 Jun 4;9(1):8287.
doi: 10.1038/s41598-019-44599-0.

An analysis of large structural variation in global Plasmodium falciparum isolates identifies a novel duplication of the chloroquine resistance associated gene

Matt Ravenhall  1 , Ernest Diez Benavente  1 , Colin J Sutherland  2 , David A Baker  1 , Susana Campino  1 , Taane G Clark  3   4
Affiliations

An analysis of large structural variation in global Plasmodium falciparum isolates identifies a novel duplication of the chloroquine resistance associated gene

Matt Ravenhall et al. Sci Rep. .

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
High quality variants by position, length and per-chromosome. (A) Distribution of deletions by size categories. (B) Distribution of duplications by size categories. (C) Distribution of distinct form of deletion across each chromosome. (D) Distribution of distinct forms of duplication across each chromosome.
Figure 2
Figure 2
Coverage plots showing examples of isolates with three types of mdr1 duplications. (A) No duplication in a Democratic Republic of Congo isolate. (B) Duplication in a Cambodian isolate. (C) Duplication in a Thai isolate; Blue traces represents the per base coverage for each isolate. Orange region indicates the predicted structural variant; Green region indicates the gene of interest, Grey indicates neighbouring genes; horizontal line is the median coverage for the isolate.
Figure 3
Figure 3
Coverage plots showing examples of isolates with three types of gch1 duplications. (A) No duplication in a Cambodian isolate. (B) Promoter duplication in a Malawian isolate. (C) Gene Duplication in a Cameroon isolate; Blue traces represent the per base coverage for each isolate. Orange region indicates the predicted structural variant; Green region indicates the gene of interest, Grey indicates neighbouring genes; horizontal line is the median coverage for the isolate.
Figure 4
Figure 4
Coverage plots showing examples of isolates with three types of crt duplications. (A) No duplication in a Bangladesh isolate. (B) Gene duplication in a Ghanaian isolate. (C) Gene duplication in a Burkina Faso isolate; Blue traces represents the per base coverage for each isolate. Orange region indicates the predicted structural variant; Green region indicates the gene of interest, Grey indicates neighbouring genes; horizontal line is the median coverage for the isolate.
See this image and copyright information in PMC

References

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