Abstract
The population genetics and structure of P. falciparum determine the rate at which malaria evolves in response to interventions such as drugs and vaccines. This has been the source of considerable recent controversy, but here we demonstrate the organism to be essentially sexual, in an area of moderately high transmission in the Lower Shire Valley, Malawi. Seven thousand mosquitoes were collected and dissected, and genetic data were obtained on 190 oocysts from 56 infected midguts. The oocysts were genotyped at three microsatellite loci and the MSP1 locus. Selfing rate was estimated as 50% and there was significant genotypic linkage disequilibrium (LD) in the pooled oocysts. A more appropriate analysis searching for genotypic LD in outcrossed oocysts and/or haplotypic LD in the selfed oocysts found no evidence for LD, indicating that the population was effectively sexual. Inbreeding estimates at MSP1 were higher than at the microsatellites, possibly indicative of immune action against MSP1, but the effect was confounded by the probable presence of null mutations. Mating appeared to occur at random in mosquitoes and evidence regarding whether malaria clones in the same host were related (presumably through simultaneous inoculation in the same mosquito bite) was ambiguous. This is the most detailed genetic analysis yet of P. falciparum sexual stages, and shows P. falciparum to be a sexual organism whose genomes are in linkage equilibrium, which acts to slow the emergence of drug resistance and vaccine insensitivity, extending the likely useful therapeutic lifespan of drugs and vaccines.
Highlights
Malaria caused by Plasmodium falciparum is a major public health problem in many countries worldwide, in sub-Saharan Africa
The chance of two haplotypes being identical in state purely by chance is a maximum of 0.160.2560.5 = 0.0125 assuming linkage disequilibrium between the loci and that separate clones in a human were derived from separate bites i.e. a human could not be infected by two genetically-related clones inoculated in the same bite
HardyWeinberg equilibrium (HWE) ARA2 showed no sign of homozygous excess and was in HWE. This analysis used material from wild mosquitoes collected by knock-down catches [17] and, oocysts will be in many different stages of development, because they usually take around 8 days following an infective blood meal to reach their maximum, mature size
Summary
Malaria caused by Plasmodium falciparum is a major public health problem in many countries worldwide, in sub-Saharan Africa. Plasmodium spp. are haploid in both human and mosquito hosts except for a brief stage in the mosquito midgut where two haploid malaria gametes present in the mosquito’s blood meal fuse to form a diploid zygote. This zygote immediately undergoes meiosis to generate four haploid cells that continue in the haploid form, reproducing through mitosis, until several thousand are present in a small sac, the oocyst, attached to the gut wall. Genetically-distinct malaria clones are often present in the same human blood meal so this sexual phase provides an opportunity for genetic recombination to occur between genetically-distinct malaria parasites, resulting in the generation of genetic diversity. We present data obtained from direct genotyping of oocysts confirming that P. falciparum is clearly a sexual organism in an area of moderate to high transmission of sub-Saharan Africa, a region that bears the brunt of malaria mortality
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