Table1_Genome-wide SNP analysis of Plasmodium falciparum shows differentiation at drug-resistance-associated loci among malaria transmission settings in southern Mali.XLSX

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.

非洲疟疾感染病例中，恶性疟原虫疟疾占据了全球负担的超过90%，其中马里是11个负担最重的国家之一，这些国家共同构成了每年感染病例的70%。尽管全球范围内进行了大规模的干预措施，恶性疟原虫的持续性依然存在，这主要归因于其遗传多样性，这种多样性驱动了其适应环境变化、发展耐药性和逃避免疫系统的能力。因此，了解恶性疟原虫在人群和干预环境中的遗传多样性对于实施消除疟疾的新策略至关重要。本研究评估了830个马里恶性疟原虫分离株（收集于2007年至2017年，来自七个地点）的12,177个高质量单核苷酸多态性（SNPs），以评估遗传变异。感染复杂性在十年间保持较高水平，在不同地点间存在差异，并呈现出整体下降的趋势。尽管没有显著的亚结构，等位基因频率在地理上存在差异，部分原因是采样时间上的变化，特别是在药物耐药性和抗原位点。在已知的药物耐药性标记（pfcrt、pfdhps、pfdhfr、pfmdr1、pfmdr2和pfk13）中，32个突变在人群中达到了至少2%的频率。位于喹诺酮类耐药性（pfmdr1和pfcrt）和抗叶酸（pfdhfr和pfdhps）主要标记内的SNPs在时间和地理上存在变化，基因组中表现出强烈的连锁不平衡和方向选择的特征。这些地理时间群体在免疫相关位点（包括E140蛋白、pfsurfin8、pfclag8、pfceltos以及pftrap）的等位基因上也存在差异，这些位点显示出种群间单倍型分化的特征。基因组中的多个区域，包括五个已知的药物耐药性位点，显示出差异性的正向选择特征。这些结果表明，药物和免疫压力是针对马里恶性疟原虫的主要选择力量，但它们对寄生虫基因组的影响在时间和空间上存在变化。在实施疟疾消除策略时，需要常规评估与这些基因组变异相互作用的干预措施。