Distinct evolutionary regimes across domains of the Plasmodium falciparum CSP gene.

Malaria disease caused by parasites of genus Plasmodium places an enormous disease burden across tropical regions of the world. The circumsporozoite protein (CSP) of Plasmodium has several key functions in binding and accessing host cells, with functions subdivided across multiple protein regions. While its key roles during infection make the gene a primary target for malaria vaccine development, the evolutionary dynamics that could affect the forecasting of useful strains remain poorly understood. We tested whether the gene undergoes multiple DNA substitution processes and whether these are divided across gene regions using a phylogenetic mixture model, and a global sample of CSP sequences specific to P. falciparum. These analyses reveal evolutionary processes unique to the central repeat region and the C-terminus. The central repeat region is dominated by synonymous substitutions (putatively neutral) and heavy C-T substitution bias, while the C-terminus undergoes mostly non-synonymous changes. These evolutionary processes are not strongly geographically restricted, and lineages from Africa and Asia where the parasite is most abundant appear to drive evolution across all CSP gene regions. We propose that insights about DNA substitution processes can help forecast the variants of importance to vaccine development, aided by state-of-the-art evolutionary modelling.