GENOME-WIDE IDENTIFICATION OF SHORT TANDEM REPEATS ASSOCIATED WITH MULTI-DRUG RESISTANCE IN Plasmodium falciparum STRAINS

Abstract

Antimalarial drug resistance in Plasmodium falciparum threatens global malaria control, and while single nucleotide polymorphisms (SNPs) are well-studied, the role of short tandem repeats (STRs) remains underexplored. This study investigates the contribution of pathogenic STRs to drug resistance using STR genotypes from HipSTR, phenotypic resistance data, and machine learning models. Allele frequency analysis revealed consistently lower alternative allele frequencies in resistant strains across all 14 chromosomes, with strong selective signals on chromosomes 2, 3, 4, 8, and 13. Population differentiation analyses (PCA, FST) identified key resistance loci near PfKelch13 and plasmepsin 2/3, along with potential novel resistance regions. A logistic regression model trained on STR alleles achieved perfect classification (AUC = 1.00), demonstrating the strong predictive power of STRs in distinguishing resistant from sensitive parasites. Top STRs showed both known and novel associations with resistance, reinforcing the polygenic nature of antimalarial resistance. These findings establish STRs as important genetic markers for resistance surveillance and highlight their potential utility in guiding malaria treatment strategies.