Gene conversion drives allelic dimorphism in two paralogous surface antigens of the malaria parasite P. falciparum

Abstract

While the malaria parasite P. falciparum has low average genome-wide diversity levels, likely due to its recent introduction from a gorilla-infecting ancestor ([~]10,000-50,000 years ago), some genes display extremely high diversity levels. In particular, certain proteins expressed on the surface of human red-blood-cell-infecting merozoites (merozoite surface proteins, MSPs) possess exactly two deeply-diverged allelic forms that have not recombined. This phenomenon, called allelic dimorphism, is of considerable interest, but its origin and maintenance remains unknown. In this study, we analysed the dimorphism in two highly-variable and paralogous MSPs, DBLMSP and DBLMSP2. Despite thousands of available Illumina WGS datasets from malaria-endemic countries, diversity in these genes has been hard to fully characterise as reads containing highly-diverged alleles fail to align to the reference genome. To solve this, we developed a pipeline leveraging genome graphs, enabling us to genotype them at high accuracy and completeness in comparison to a state-of-the-art GATK-based pipeline. Using our newly-resolved sequences we found both genes are dimorphic in a specific protein domain (DBL), and that one of the two forms is shared across the genes. We identified clear evidence of non-allelic gene conversion between the two genes as the likely mechanism behind sharing, leading us to propose a new model for allelic dimorphism through gene conversion between diverged paralogs. This model is consistent with high diversity levels in these two genes despite the strong historical P. falciparum transmission bottleneck.