Genome-wide SNP analysis of Plasmodium falciparum shows differentiation at drug-resistance-associated loci among malaria transmission settings in southern Mali

Abstract

Plasmodium falciparum malaria cases in Africa represent over 90% of the global burden with Mali being amongst the 11 highest burden countries that account for 70% of this annual incidence. The persistence of P. falciparum despite massive global interventions is because of its genetic diversity that drives its ability to adapt to environmental changes, develop resistance to drugs, and evade the host immune system. Knowledge on P. falciparum genetic diversity across populations and intervention landscape is thus critical for the implementation of new strategies to eliminate malaria. This study assessed genetic variation with 12,177 high-quality SNPs from 830 Malian P. falciparum isolates collected between 2007 and 2017 from seven locations. The complexity of infections remained high, varied between sites, and showed a trend toward overall decreasing complexity over the decade. Though there was no significant substructure, allele frequencies varied geographically, partly driven by temporal variance in sampling, particularly for drug resistance and antigen loci. Thirty-two mutations in known drug resistance markers (pfcrt, pfdhps, pfdhfr, pfmdr1, pfmdr2, and pfk13) attained a frequency of at least 2% in the populations. SNPs within and around the major markers of resistance to quinolines (pfmdr1 and pfcrt) and antifolates (pfdhfr and pfdhps) varied temporally and geographically, with strong linkage disequilibrium and signatures of directional selection in the genome. These geo-temporal populations also differentiated at alleles in immune-related loci, including, protein E140, pfsurfin8, pfclag8, and pfceltos, as well as pftrap, which showed signatures of haplotype differentiation between populations. Several regions across the genomes, including five known drug resistance loci, showed signatures of differential positive selection. These results suggest that drugs and immune pressure are dominant selective forces against P. falciparum in Mali, but their effect on the parasite genome varies temporally and spatially. Interventions interacting with these genomic variants need to be routinely evaluated as malaria elimination strategies are implemented.

Genome-wide genetic variation and molecular surveillance of drug resistance in Plasmodium falciparum isolates from asymptomatic individuals in Ouélessébougou, Mali

“…On a maximum-likelihood tree, Ouélessébougou and other Malian isolates cluster with West-African populations, as expected. Despite a recent report observing decreasing multiplicity of infection from 2007 to 2017 in Mali 16 , our findings show a higher multiclonality in 2019-2020 than in isolates from different sites where collection took place between 2015 and 2017. There may be multiple explanations for the highly multiclonal status of the study parasite population, such as the high P. falciparum incidence rates in this region (Fig.…”

“…We also observed increased frequencies of molecular markers for sulfadoxine-pyrimethamine and lumefantrine resistance, compared to older Malian isolates. Genomes from Malian P. falciparum isolates collected between 2007 and 2017 have previously been generated 16,26 . However, a more up-to-date and systematic sampling strategy is required to support efforts toward infection control and elimination.…”

Genetic characterization of the Entamoeba moshkovskii population based on different potential genetic markers

“…In contrast, the chitinase of E. histolytica is highly polymorphic and contains STR units, whereas the chitinase of E. moshkovskii is not a highly polymorphic gene as observed in this study (Das et al, 2014). The reported SNPs could potentially play a role in drug sensitivity in E. moshkovskii, similar to how certain SNPs have been linked to multidrug resistance in Plasmodium falciparum, as reported by Coulibaly et al (2022). Recombination events were only identified at the apc locus.…”

“…The reported SNPs could potentially play a role in drug sensitivity in E. moshkovskii , similar to how certain SNPs have been linked to multidrug resistance in Plasmodium falciparum , as reported by Coulibaly et al . ( 2022 ).…”

Complexity of Plasmodium falciparum infection and genetic variations associated with differences in parasite clearance time in two Malian villages

“…Highly complex infections results from high diversity in P. falciparum population as observed in high transmission settings, while low transmission settings are characterized by more monoclonal infections [ 28 , 29 ]. Complex infections remain highly prevalent in Mali but this varies between different geographic areas [ 30 , 31 ]. At baseline the median number of parasite clones per infection was twice as high compared to previous medians reported respectively in Mali and Burkina Faso [ 31 , 32 ].…”