Role for gene conversion in the evolution of cell-surface antigens of the malaria parasite Plasmodium falciparum

PLoS Biol. 2024 Mar 7;22(3):e3002507. doi: 10.1371/journal.pbio.3002507. eCollection 2024 Mar.


While the malaria parasite Plasmodium falciparum has low average genome-wide diversity levels, likely due to its recent introduction from a gorilla-infecting ancestor (approximately 10,000 to 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 2 deeply diverged lineages that have seemingly not recombined. While of considerable interest, the evolutionary origin of this phenomenon remains unknown. In this study, we analysed the genetic diversity of 2 of the most variable MSPs, DBLMSP and DBLMSP2, which are paralogs (descended from an ancestral duplication). Despite thousands of available Illumina WGS datasets from malaria-endemic countries, diversity in these genes has been hard to characterise as reads containing highly diverged alleles completely 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. Using our newly- resolved sequences, we found that both genes exhibit 2 deeply diverged lineages in a specific protein domain (DBL) and that one of the 2 lineages is shared across the genes. We identified clear evidence of nonallelic gene conversion between the 2 genes as the likely mechanism behind sharing, leading us to propose that gene conversion between diverged paralogs, and not recombination suppression, can generate this surprising genealogy; a model that is furthermore consistent with high diversity levels in these 2 genes despite the strong historical P. falciparum transmission bottleneck.

MeSH terms

  • Animals
  • Antigens, Surface
  • Gene Conversion
  • Genetic Variation
  • Hominidae*
  • Humans
  • Malaria* / parasitology
  • Malaria, Falciparum*
  • Parasites* / metabolism
  • Plasmodium falciparum / metabolism
  • Protozoan Proteins / genetics
  • Protozoan Proteins / metabolism


  • Antigens, Surface
  • Protozoan Proteins

Grants and funding

BL was funded by a predoctoral fellowship from the European Molecular Biology Laboratory. ZI was funded by a Wellcome Trust/Royal Society Sir Henry Dale Fellowship, grant number 102541/A/13/Z. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.