Evolutionary trade-offs between functional and immune selection shape multigene families in pathogens

Many infectious pathogens employ rapidly diversifying multigene families to encode surface proteins that influence fitness in both a frequency-dependent and an absolute manner, through respective variation in antigenic determinants and the basic reproductive number (R ₀ ). How evolution shapes gene composition as pathogens compete for hosts remains largely unexplored, even though these two trait axes map to those of Modern Coexistence Theory. We address this question with a stochastic computational model for the transmission of the Plasmodium falciparum parasite and the birth-death gene dynamics of the var multigene family encoding for its major surface antigen. Selection alone cannot maintain the stable ratio observed for two gene groups within parasite genomes, suggesting that group-based classifications do not clearly reflect transmission strategy and virulence. When a trade-off exists between the two axes, strong immune selection attenuates functional selection for traits associated with absolute fitness and favors fast-recombining genes for antigenic diversification. Thus, the proportion of high-R ₀ genes in individual genomes (and in the population) inverts along the transmission intensity gradient, with differences between genes becoming increasingly frequency-dependent. Overall, strong immune selection increases invasion probability of novel antigens and niche differences between parasite genomes, while reducing gene variance in transmissibility, virulence and infection duration.