Module-level recombination drives DBLMSP polymorphism and functional conservation in Plasmodium falciparum.

The DBLMSP gene family in Plasmodium falciparum encodes surface antigens involved in immune evasion and red blood cell invasion, yet its extensive polymorphism has long defied straightforward classification. While analyzing DBLMSP1 sequences from samples collected along the China-Myanmar border, we found that haplotypes could not be readily explained by standard population genetic models. Instead, comparative alignment and BLAST analysis revealed that DBLMSP1 and DBLMSP2 consist of discrete, recombinable sequence modules, flanked by conserved upstream and downstream regions. This led us to propose a modular framework that redefines allele structure as combinations of well-defined building blocks with consistent boundaries and positional constraints. Through global mining of DBLMSP sequences, we identified nine genotypes each for DBLMSP1 and DBLMSP2, with modules labeled sequentially (e.g., 1M2a, 1M3c, and 2M3b). Some modules were shared across paralogs, notably the identical sequence of DBLMSP1 module 1M3c and DBLMSP2 module 2M3a, suggesting historical inter-locus recombination. In the dominant genotype DBLMSP1-1, nucleotide diversity and Tajima's D peaked within variable modules, whereas conserved structural elements, including the receptor-binding cleft and SPAM domain, were under purifying selection. Patterns of long-range linkage disequilibrium aligned with module junctions, suggesting that modular structure may shape recombination patterns independently of selection. Modular recombination has been widely recognized in viral systems and multigene families such as var, but its relevance in DBLMSPs has been underappreciated. By applying this framework to P. falciparum DBLMSPs, we aim to provide a useful perspective for understanding their structural diversity and evolutionary dynamics, with implications for immunogen design and parasite surveillance.