Large deletion variants in a Plasmodium falciparum ookinete protein gene and associations with different endemic populations and mosquito vectors

The Plasmodium falciparum PIMMS43 gene encodes an ookinete protein that is important for mosquito infection. Here, large indel variants within the coding sequence are identified, and frequencies in natural infections of humans and mosquitoes investigated. Comparing long-read genome sequences in a small panel of P. falciparum strains and related species revealed a 150 bp deletion in the central part of the gene in several strains including the standard 3D7 reference genome. Mapping of short-read genome sequence data from 524 P. falciparum infections from nine different countries to full-length PIMMS43 showed the 150 bp deletion and an alternative 90 bp deletion to be common structural variants. Across African populations, the 150 bp deletion had a mean allele frequency of 32%, and the 90 bp deletion a mean frequency of 12%, with significant geographical variation. Targeted genotyping of 30 oocysts from naturally infected mosquitoes in Tanzania by nested PCR showed overall deletion variant frequencies similar to those seen in human infections in the same country. Although sample size was limited, a difference in the variant frequencies in oocysts from Anopheles gambiae and Anopheles funestus suggests potential vector-specific selection. The findings highlight the importance of surveying structural genomic variation and its potential role in parasite adaptation. Data summaryThe long-read genome sequence data sources are listed in the Supplementary Information (Supplementary Table 1). The short-read genome sequence data from human infections were extracted as a selected subset of those in the Pf7 release of global data from the MalariaGEN Consortium as described in the Methods. The SNP and indel genotypes derived from each sample of parasites cultured in the laboratory and from natural mosquito infections are given in the Supplementary Information (Supplementary Tables 1 and 3, Supplementary Figure 1). Impact statementThis study identifies large indel polymorphisms in the malaria parasite transmission-stage gene PIMMS43, reflecting substantial structural variation previously overlooked by genome-wide SNP-focused analyses. Using long- and short-read genomic data across diverse samples followed by targeted genotyping, we show that deletion variants are frequent and geographically structured, with initial evidence consistent with potential vector-specific selection. This highlights the importance of incorporating structural variation into population genomic surveillance and studies of parasite adaptation.