Heterogeneous constraint and adaptation across the malaria parasite life cycle.

Evolutionary forces vary across genomes, creating disparities in how traits evolve. In organisms with complex life cycles, it is unclear how intrinsic differences among discrete life stages impact evolution. Here, we look for life history-driven patterns of adaptation in Plasmodium falciparum, a malaria-causing parasite with a multi-stage life cycle. We posit that notable differences across the P. falciparum life cycle-including cell ploidy, the extent of clonal competition and the presence of transmission bottlenecks-alter the drift-selection balance acting at discrete life stages. Categorizing genes by their stages of expression, we compare patterns of between- and within-species diversity across stages. Most notably, we find signals of weaker negative selection in genes exclusively expressed in sporozoites. This matches theoretical expectations as sporozoites do not proliferate, show limited evidence of clonal competition, and pass through a strong bottleneck. We discuss how the timing of therapeutic interventions towards particular life stages might impact the rate at which parasite populations evolve resistance and consider the functional, molecular and population genetic factors that could contribute to these patterns.