Genome-Wide Scans for Ghanaian Plasmodium falciparum Genes Under Selection From Local and Chinese Host Populations

Abstract

Initial malarial infection mostly causes symptomatic illness in humans. Infection that is not fatal induces complete protection from severe illness and death, and thus complete protection from severe illness or death is granted with sufficient exposure. However, malaria parasite immunity necessitates constant exposure. Therefore, it is important to evaluate lowered immunity and recurrent susceptibility to symptomatic disease in lower transmission areas. We aimed to investigate selection pressure based on transmission levels, antimalarial drug use, and environmental factors. We whole genome sequenced (WGS) P. falciparum clinical samples from Chinese hosts working in Ghana and compared the results with the WGS data of isolates from native Ghanaians downloaded from pf3k. The P. falciparum samples were generally clustered according to their geographic origin, and Chinese imported samples showed a clear African origin with a slightly different distribution from the native Ghanaian samples. Moreover, samples collected from two host populations showed evidence of differences in the intensity of selection. Compared with native Ghanaian samples, the China-imported isolates exhibited a higher proportion of monoclonal infections, and many genes associated with RBC invasion and immune evasion were found to be under less selection pressure. There was no significant difference in the selection of drug-resistance genes due to a similar artemisinin-based combination therapy medication profile. Local selection of malarial parasites is considered to be a result of differences in the host immunity or disparity in the transmission opportunities of the host. In China, most P. falciparum infections were imported from Africa, and under these circumstances, distinct local selective pressures may be caused by varying acquired immunity and transmission intensity. This study revealed the impact of host switching on the immune system, and it may provide a better understanding of the mechanisms that enable clinical immunity to malaria.

Keywords: Ghana; Plasmodium falciparum; acquired immunity; imported malaria; positive selection; variant surface antigen.

Figure 1

Parasite population structure in nine China-imported samples relative to the reference. (A) Principal component analysis (PCA) plots illustrating the genetic differentiation between populations around the world. (B) Within Ghanaian population, samples collected from different hosts were divided along the secondary axis. (C) ADMIXTURE bar plot illustrates the population structure within Ghanaian populations from local and Chinese hosts at an optimized cluster value of K = 5.

Figure 2

F _ST value of all genes summarizing the difference between China-imported samples (n=9) and native Ghanaian (n=92) reference samples. (A) The variation profile of some gene families exhibited greater genetic diversity between imported and local samples. (B) F _ST value of each gene from two subgroups of the rif family showed significant differences. (C) F _ST value in all genes for pairs of populations to explore genomic effects of local and overseas hosts.

Figure 3

Tajima’s D value of all genes summarizing the difference of balanced selection between China-imported samples (n=9) and native Ghanaian (n=92) reference samples. The lower mean value in local samples suggested a stronger selection pressure from African hosts. (A) Some important genes/gene families showed the same trend as that of the gene background, and these genes/gene families include phist, 2TM, msp1, and drug-resistance genes. (B) Unlike the background, there was not much difference in variant surface antigen (VSA) gene families between the imported and local groups.

Figure 4

Haplotype-based detected positive selection in China-imported samples. (A) Genome-wide scan of standardized |iHS| for single nucleotide polymorphisms (SNPs) with a minor allele frequency (MAF) of at least 5% in imported samples. Dashed lines indicate the top 1% and 5% of |iHS| values (|iHS| score >2.49 and 1.82, respectively). SNPs from important gene or gene families with top values were listed. (B) Genome-wide scan of standardized XP-EHH for SNPs with a MAF of at least 5% in China-imported samples, using native Ghanaian samples as the reference population. Dashed lines indicate the top 1% of XP-EHH values (± 0.5%, XP-EHH score >2.29 or <-3.39 in imported/local populations). SNPs from the VAS gene family with top ranking values were listed.