Abstract
Locally varying selection on pathogens may be due to differences in drug pressure, host immunity, transmission opportunities between hosts, or the intensity of between-genotype competition within hosts. Highly recombining populations of the human malaria parasite Plasmodium falciparum throughout West Africa are closely related, as gene flow is relatively unrestricted in this endemic region, but markedly varying ecology and transmission intensity should cause distinct local selective pressures. Genome-wide analysis of sequence variation was undertaken on a sample of 100 P. falciparum clinical isolates from a highly endemic region of the Republic of Guinea where transmission occurs for most of each year and compared with data from 52 clinical isolates from a previously sampled population from The Gambia, where there is relatively limited seasonal malaria transmission. Paired-end short-read sequences were mapped against the 3D7 P. falciparum reference genome sequence, and data on 136,144 single nucleotide polymorphisms (SNPs) were obtained. Within-population analyses identifying loci showing evidence of recent positive directional selection and balancing selection confirm that antimalarial drugs and host immunity have been major selective agents. Many of the signatures of recent directional selection reflected by standardized integrated haplotype scores were population specific, including differences at drug resistance loci due to historically different antimalarial use between the countries. In contrast, both populations showed a similar set of loci likely to be under balancing selection as indicated by very high Tajima’s D values, including a significant overrepresentation of genes expressed at the merozoite stage that invades erythrocytes and several previously validated targets of acquired immunity. Between-population FST analysis identified exceptional differentiation of allele frequencies at a small number of loci, most markedly for five SNPs covering a 15-kb region within and flanking the gdv1 gene that regulates the early stages of gametocyte development, which is likely related to the extreme differences in mosquito vector abundance and seasonality that determine the transmission opportunities for the sexual stage of the parasite.
Highlights
Evolution is driven by changing forces of selection acting upon genomes, with populations experiencing particular selective events in each generation (Olson-Manning et al 2012)
High-quality sequence data obtained from 100 P. falciparum clinical isolates collected from the N’Zerekore area of Guinea enabled identification of 99,305 single nucleotide polymorphisms (SNPs) that were polymorphic in the population
Coding sequences had higher read coverage compared with intergenic regions, as expected, due to less extreme A + T nucleotide richness, and as a result, 68% of all SNPs called were located within genes
Summary
Evolution is driven by changing forces of selection acting upon genomes, with populations experiencing particular selective events in each generation (Olson-Manning et al 2012). Strong selection operates on malaria parasites, and their study is facilitated by a relatively small eukaryotic genome (~23 Mb), enabling genome-wide sequence analysis of many clinical isolates of the major human parasite Plasmodium falciparum (Manske et al 2012; Miotto et al 2013). Initial scans for evidence of positive selection on P. falciparum by analysis of individual endemic populations have clearly identified loci that have undergone selective sweeps, from antimalarial drug use (Chang et al 2012; Cheeseman et al 2012; Park et al 2012; Miotto et al 2013; Nwakanma et al 2014; Takala-Harrison et al 2013), as well as loci that are apparently under balancing selection, including ß The Author 2014.
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