Genomic evolution of epitopes and low complexity regions in Plasmodium

Despite decades-long efforts to eradicate malaria, there is no effective anti-malarial vaccine. The genomic complexity of Plasmodium, the agent of malaria, is known to pose major challenges for vaccine development because it allows the pathogen to quickly change. Genomic changes over time are the realm of evolutionary biology, yet these pathogens remain poorly understood from an evolutionary perspective. Understanding the evolution of the pathogen’s immunity, particularly of immunogenic regions such as epitopes, may help uncover effective targets for anti-malarial vaccines. Here we examined the evolutionary history of epitopes and epitope-like regions to determine whether they share underlying evolutionary mechanisms and potential functions relevant to the pathogen’s interactions with the host immune response. Our comparative sequence analyses contrasted patterns of sequence conservation, amino acid composition, and protein structure of epitopes and low complexity regions (LCRs) in 21 Plasmodium species. Our results revealed similarities in amino acid composition and preferred secondary structures between epitopes and LCRs; however, we also identified differences in evolutionary trends where LCRs exhibit overall lower conservation and higher disorder. We also found that epitopes and LCRs have a wide array of configurations, with various levels of conformations and structural orders. We propose that combinations of different levels of conservation and order between epitopes and LCRs in the same gene play a role in maintaining the functional integrity required by the pathogen along with the variability necessary to evade the host immune response. In particular, LCRs that are variable and disordered may be an evolutionary necessity for Plasmodium to maintain conserved epitopes, while LCRs that are conserved may serve currently unknown function(s) and deserve to be examined in greater detail. Our findings show there may be more candidate targets for future anti-malarial treatments than currently known and that some of these targets may work across strains and species.