Modeling the genetic relatedness of Plasmodium falciparum parasites following meiotic recombination and cotransmission

January 9, 2018

Abstract: 

Background

Unlike in most pathogens, multiple-strain (polygenomic) infections of P. falciparum are frequently composed of genetic siblings. These genetic siblings are the result of sexual reproduction and can coinfect the same host when cotransmitted by the same mosquito. The degree with which coinfecting strains are related varies among infections and populations. Because sexual recombination occurs within the mosquito, the relatedness of cotransmitted strains could depend on transmission dynamics, but little is actually known of the factors that influence the relatedness of cotransmitted strains. Part of the uncertainty stems from an incomplete understanding of how within-host and within-vector dynamics affect cotransmission. Cotransmission is difficult to examine experimentally but can be explored using a computational model. We developed a malaria transmission model that simulates sexual reproduction in order to understand what determines the relatedness of cotransmitted strains. This study highlights how the relatedness of cotransmitted strains depends on both within-host and within-vector dynamics including the complexity of infection. We also used our transmission model to analyze the genetic relatedness of polygenomic infections following a series of multiple transmission events and examined the effects of superinfection. Understanding the factors that influence the relatedness of cotransmitted strains could lead to a better understanding of the population-genetic correlates of transmission and therefore be important for public health.

Results

We used our meiosis simulations to quantify the relatedness of sporozoites described by each possible pedigree. Based on the parental ancestries described by our nine pedigrees and the estimate of relatedness provided by our meiosis simulation, we also grouped parasites using kinship definitions. These kinship definitions are analogous to those used in diploid organisms and have been used in other IBD analyses [5]. However, we found that sporozoites sampled from a single, outcrossed oocyst (pedigree 3) could not be described by existing kinship categories. Because they originate from the same meiotic event, we describe their kinship as “meiotic siblings.” Although the average relatedness of meiotic siblings is 0.5, our meiosis simulation revealed that the distribution is bimodal, with one mode at 1.0 (the expected relatedness of genetically identical meiotic siblings) and one mode at 0.33 (the expected relatedness of genetically distinct meiotic siblings) (S3 Fig). Our pedigree/kinship framework and meiosis simulation results are summarized in Fig 2.

Fig. 2

The 9 possible pedigrees describing parasite pairs. Pedigrees represent the genetic ancestry of parasites and the oocysts they are sampled from. Circles at the top of each pedigree represent the gametes that fuse and undergo meiosis while circles at the bottom represent the sporozoites that are generated following meiosis and expansion in the oocyst. Different colors represent different genomes. Sporozoites with mixed colors indicate they are the result of outcrossing. Blue arrows between pedigrees indicate that sporozoites are sampled from different oocysts. Parasites can be sampled from the same oocyst (pedigrees 1 and 2) or from multiple oocysts (pedigrees 3–9). For pedigree 2, the distribution of expected relatedness was bimodal, and we provide the average across the entire distribution (top) as well as the two modes (bottom). Pedigree 6 and 8 are only accessible when COI ≥ 3 and pedigree 9 is only accessible when COI ≥ 4.