Abstract
In their competition for hosts, parasites with antigens that are novel to the host immune system will be at a competitive advantage. The resulting frequency-dependent selection can structure parasite populations into strains of limited genetic overlap. For the causative agent of malaria, Plasmodium falciparum, the high recombination rates and associated vast diversity of its highly antigenic and multicopy var genes preclude such clear clustering in endemic regions. This undermines the definition of strains as specific, temporally persisting gene variant combinations. We use temporal multilayer networks to analyze the genetic similarity of parasites in both simulated data and in an extensively and longitudinally sampled population in Ghana. When viewed over time, populations are structured into modules (i.e., groups) of parasite genomes whose var gene combinations are more similar within than between the modules and whose persistence is much longer than that of the individual genomes that compose them. Comparison to neutral models that retain parasite population dynamics but lack competition reveals that the selection imposed by host immunity promotes the persistence of these modules. The modular structure is, in turn, associated with a slower acquisition of immunity by individual hosts. Modules thus represent dynamically generated niches in host immune space, which can be interpreted as strains. Negative frequency-dependent selection therefore shapes the organization of the var diversity into parasite genomes, leaving a persistence signature over ecological time scales. Multilayer networks extend the scope of phylodynamics analyses by allowing quantification of temporal genetic structure in organisms that generate variation via recombination or other non-bifurcating processes. A strain structure similar to the one described here should apply to other pathogens with large antigenic spaces that evolve via recombination. For malaria, the temporal modular structure should enable the formulation of tractable epidemiological models that account for parasite antigenic diversity and its influence on intervention outcomes.
Highlights
The dynamic arms race between hosts and pathogens sets the stage for a selective advantage of rare variants that confer either immune protection to hosts or immune escape to pathogens and a corresponding disadvantage of common ones
Can strains exist and persist in such vast antigenic spaces? What is a strain in dynamic systems undergoing recombination at the level of both the genes themselves and the genomes they compose? A key characteristic signature of immune selection would involve the persistence of gene combinations over longer time scales than expected under neutrality [4], a hypothesis that remains to be examined despite its relevance for the existence and definition of strains themselves
We address this temporal dimension by examining the role frequency dependence plays in maintaining gene combinations over time in the highly diverse multicopy var gene family of P. falciparum
Summary
The dynamic arms race between hosts and pathogens sets the stage for a selective advantage of rare variants that confer either immune protection to hosts or immune escape to pathogens and a corresponding disadvantage of common ones. This frequency-dependent effect can act as a form of balancing selection and is a powerful force promoting high antigenic diversity and maintaining polymorphisms significantly longer than neutral drift. The role of immune selection at this higher level of organization remains, poorly understood and documented, especially in pathogens whose antigenic variation involves vast diversity generated via recombination within the genome or between different genomes, as is the case in several bacteria, protozoa, and fungi [3]. Can strains exist and persist in such vast antigenic spaces? What is a strain in dynamic systems undergoing recombination at the level of both the genes themselves and the genomes they compose? A key characteristic signature of immune selection would involve the persistence of gene combinations over longer time scales than expected under neutrality [4], a hypothesis that remains to be examined despite its relevance for the existence and definition of strains themselves
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