Signatures of competition and strain structure within the major blood‐stage antigen of <i>Plasmodium falciparum</i> in a local community in Ghana

Rorick, Mary M.; Artzy‐Randrup, Yael; Ruybal‐Pesántez, Shazia; Tiedje, Kathryn E.; Rask, Thomas S.; Oduro, Abraham; Ghansah, Anita; Koram, Kwadwo A.; Day, Karen P.; Pascual, Mercedes

doi:10.1002/ece3.3803

Cited by 13 publications

(27 citation statements)

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“…The pattern in Fig 7 is a form of nonrandom structure in the functional composition of var types within this population. This form of nonrandom structure may be related to other forms of nonrandom structure within the distribution of var types in this population, which we have reported previously [ 35 ]. Larger field-sampled datasets of var diversity collected in subsequent studies of this population may in the future be able to address the possible connection between these different forms of non-random structure within the var antigenic types of this population.…”

Section: Resultssupporting

confidence: 70%

“…Distinct isolates become more comparable when there is significant overlap among their antigenic repertoires, and the distribution of overlap indices within the population as a whole becomes more interesting. The overlap that exists among distinct antigenic types circulating in a local population is a critical feature for studying certain epidemiological and ecological dynamics [ 35 ]. HBFG types may therefore be useful for future studies of these dynamics.…”

Section: Discussionmentioning

confidence: 99%

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Identifying functional groups among the diverse, recombining antigenic var genes of the malaria parasite Plasmodium falciparum from a local community in Ghana

et al. 2018

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A challenge in studying diverse multi-copy gene families is deciphering distinct functional types within immense sequence variation. Functional changes can in some cases be tracked through the evolutionary history of a gene family; however phylogenetic approaches are not possible in cases where gene families diversify primarily by recombination. We take a network theoretical approach to functionally classify the highly recombining var antigenic gene family of the malaria parasite Plasmodium falciparum. We sample var DBLα sequence types from a local population in Ghana, and classify 9,276 of these variants into just 48 functional types. Our approach is to first decompose each sequence type into its constituent, recombining parts; we then use a stochastic block model to identify functional groups among the parts; finally, we classify the sequence types based on which functional groups they contain. This method for functional classification does not rely on an inferred phylogenetic history, nor does it rely on inferring function based on conserved sequence features. Instead, it infers functional similarity among recombining parts based on the sharing of similar co-occurrence interactions with other parts. This method can therefore group sequences that have undetectable sequence homology or even distinct origination. Describing these 48 var functional types allows us to simplify the antigenic diversity within our dataset by over two orders of magnitude. We consider how the var functional types are distributed in isolates, and find a nonrandom pattern reflecting that common var functional types are non-randomly distinct from one another in terms of their functional composition. The coarse-graining of var gene diversity into biologically meaningful functional groups has important implications for understanding the disease ecology and evolution of this system, as well as for designing effective epidemiological monitoring and intervention.

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Section: Resultssupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Identifying functional groups among the diverse, recombining antigenic var genes of the malaria parasite Plasmodium falciparum from a local community in Ghana

et al. 2018

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“…falciparum , recent work allowing for realistic levels of genetic diversity comparable to that found in endemic high transmission regions of sub-Saharan Africa resulted in a more complex similarity structure clearly distinguishable from patterns generated under neutrality but that can no longer be described by distinct clusters [15]. Deep sampling and sequencing of var gene isolates from asymptomatic human populations within a given time window or transmission season have confirmed these nonrandom patterns that are also non-neutral, in the sense that they cannot be simply explained by stochastic extinction, immigration, and transmission in the absence of acquired immune memory and therefore competition of parasites for hosts [15–17]. The lack of explicit consideration of the temporal dimension in the analysis of structure, despite the highly dynamic nature of the P .…”

Section: Introductionmentioning

confidence: 99%

Competition for hosts modulates vast antigenic diversity to generate persistent strain structure in Plasmodium falciparum

Pilosof

Tiedje

et al. 2019

PLoS Biol

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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.

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“…Each parasite genome has a 'repertoire' of 50-60 unique var gene copies, sequentially expressed to produce different variants of PfEMP1 during infection. In endemic regions of high transmission, var genes exhibit enormous diversity [16,17,19] resulting from evolutionary innovation at two levels of organization. At the gene level, var gene variants can be generated through both mutation and ectopic recombination [20,21], with tens of thousands of variants documented in local populations [16].…”

Section: Resultsmentioning

confidence: 99%

“…For P. falciparum, recent work allowing for realistic levels of genetic diversity comparable to that found in endemic high transmission regions of sub-Saharan Africa, resulted in a more complex similarity structure clearly distinguishable from patterns generated under neutrality but that can no longer be described by distinct clusters [15]. Deep sampling and sequencing of var gene isolates from asymptomatic human populations within a given time window or transmission season, have confirmed these non-random patterns that are also non-neutral, in the sense that they cannot be simply explained by stochastic extinction, immigration, and transmission in the absence of acquired immune memory and therefore, competition of parasites for hosts [15][16][17]. The lack of explicit consideration of the temporal dimension may be the reason why no apparent distinct clustering was identified, and is the motivation behind this work.…”

Section: Introductionmentioning

confidence: 88%

Competition for hosts modulates vast antigenic diversity to generate persistent strain structure in Plasmodium falciparum

Pilosof

Tiedje

et al. 2018

Preprint

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In their competition for hosts, parasites with antigens that are novel to host immunity will be at a competitive advantage. The resulting frequency-dependent selection can structure parasite populations into strains of limited genetic overlap. For Plasmodium falciparum-the causative agent of malaria-in endemic regions, the high recombination rates and associated vast diversity of its highly antigenic and multicopy var genes preclude such clear clustering; 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. SignificanceMany pathogens, including the causative agent of malaria Plasmodium falciparum, use antigenic variation, obtained via recombination, as a strategy to evade the human immune system. The vast diversity and multiplicity of genes encoding antigenic variation in high transmission regions challenge the notion of the existence of distinct strains: temporallypersistent and specific combinations of genes relevant to epidemiology. We examine the role of human immune selection in generating such genetic population structure in the major blood-stage antigen of Plasmodium falciparum. We show, using simulated and empirical data, that immune selection generates and maintains 'modules' of genomes with higher genetic similarity within, than between, these groups. Selection further promotes the persistence of these modules for much longer times than those of their constituent genomes. Simulations show that the tempora...

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Signatures of competition and strain structure within the major blood‐stage antigen of Plasmodium falciparum in a local community in Ghana

Cited by 13 publications

References 58 publications

Identifying functional groups among the diverse, recombining antigenic var genes of the malaria parasite Plasmodium falciparum from a local community in Ghana

Identifying functional groups among the diverse, recombining antigenic var genes of the malaria parasite Plasmodium falciparum from a local community in Ghana

Competition for hosts modulates vast antigenic diversity to generate persistent strain structure in Plasmodium falciparum

Competition for hosts modulates vast antigenic diversity to generate persistent strain structure in Plasmodium falciparum

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