Center for Computational Molecular Biology, Brown University, Providence, United States; Warren Alpert Medical School, Brown University, Providence, United States
Neeva WernsmanYoung
Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, United States
Sin Ting Hui
Department of Pathology and Laboratory Medicine, Brown University, Providence, United States
Rebecca Crudale
Department of Pathology and Laboratory Medicine, Brown University, Providence, United States
Emily Y Liang
Department of Pathology and Laboratory Medicine, Brown University, Providence, United States
Christian P Nixon
Department of Pathology and Laboratory Medicine, Brown University, Providence, United States
David Giesbrecht
Department of Pathology and Laboratory Medicine, Brown University, Providence, United States
Jonathan J Juliano
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, United States; Division of Infectious Diseases, Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, United States; Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, United States
Jonathan B Parr
Division of Infectious Diseases, Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, United States; Curriculum in Genetics and Molecular Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, United States
Center for Computational Molecular Biology, Brown University, Providence, United States; Warren Alpert Medical School, Brown University, Providence, United States; Department of Pathology and Laboratory Medicine, Brown University, Providence, United States
Most malaria rapid diagnostic tests (RDTs) detect Plasmodium falciparum histidine-rich protein 2 (PfHRP2) and PfHRP3, but deletions of pfhrp2 and phfrp3 genes make parasites undetectable by RDTs. We analyzed 19,313 public whole-genome-sequenced P. falciparum field samples to understand these deletions better. Pfhrp2 deletion only occurred by chromosomal breakage with subsequent telomere healing. Pfhrp3 deletions involved loss from pfhrp3 to the telomere and showed three patterns: no other associated rearrangement with evidence of telomere healing at breakpoint (Asia; Pattern 13-TARE1); associated with duplication of a chromosome 5 segment containing multidrug-resistant-1 gene (Asia; Pattern 13-5++); and most commonly, associated with duplication of a chromosome 11 segment (Americas/Africa; Pattern 13-11++). We confirmed a 13–11 hybrid chromosome with long-read sequencing, consistent with a translocation product arising from recombination between large interchromosomal ribosome-containing segmental duplications. Within most 13-11++ parasites, the duplicated chromosome 11 segments were identical. Across parasites, multiple distinct haplotype groupings were consistent with emergence due to clonal expansion of progeny from intrastrain meiotic recombination. Together, these observations suggest negative selection normally removes 13-11++pfhrp3 deletions, and specific conditions are needed for their emergence and spread including low transmission, findings that can help refine surveillance strategies.
