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Abstract
Understanding the origins and consequences of biodiversity in highly diverse systems is a central goal in community and disease ecology. This thesis investigates the eco-evolutionary dynamics of the malaria parasite Plasmodium falciparum, focusing on strain hyperdiversity and population structure from the perspective of the hyperdiverse var multigene family, which encodes the major variant surface antigen expressed during the blood stage of infection. Although this extreme diversity underlies antigenic variation and immune evasion, its consequences, and the eco-evolutionary feedback that sustain it, for the parasite’s response to intervention remain poorly understood. To address this gap, my work integrates agent-based modeling and statistical inference, adopting a phylodynamics-inspired framework grounded in strain theory to examine how var gene diversity and the associated strain hyperdiversity shape malaria’s population dynamics and its response to transmission-reducing interventions. In Chapter 1, I develop a stochastic agent-based model to investigate how malaria transmission systems in high-transmission endemic regions respond to transmission-reducing interventions. The results reveal nonlinear rebound dynamics along a transmission gradient and identify molecular early-warning indicators, derived from deep sampling of var genes, that signal the system’s approach to transitions between highly resilient and fragile, extinction-prone epidemiological states. In Chapter 2, I design a Bayesian framework to infer the multiplicity of infection (MOI), the number of genetically distinct parasite strains co-infecting a host, from var gene sequence data, providing a quantitative measure of within-host infection complexity. Chapter 3 extends this work by applying two queueing-theory methods to derive the force of infection (FOI) from MOI, offering a tractable approach to estimate transmission intensity directly from molecular data. Finally, Chapter 4 investigates how directional functional selection on traits related to absolute fitness, such as virulence, transmissibility, and duration of expression, interacts with negative frequency-dependent immune selection on traits related to antigenic variation, including the mitotic recombination rate. My work examines how these selective forces, with or without trade-offs among traits, jointly shape the coexistence and distribution of var genes differing in these traits within parasite genomes and in the population along a transmission gradient. These findings inform the interpretation of var gene diversity and the identification of clinically important gene subsets from sequencing data. Together, these chapters demonstrate that the diversity of the var multigene family is fundamental to malaria’s epidemiological resilience and adaptive potential in the face of transmission-reducing interventions. By linking molecular, ecological, and evolutionary processes, this thesis advances a unified framework that connects the parasite’s genomic architecture to population-level transmission dynamics. The results highlight how surveillance that incorporates antigen-encoding regions, rather than relying solely on neutral genetic markers, can improve predictions of system transitions, rebound risks, and prospects for elimination in high-transmission endemic regions where intervention remains challenging. More broadly, the eco-evolutionary principles underlying malaria’s dynamics extend to other infectious diseases with antigens encoded by multigene families and similar epidemiological characteristics.