Interchromosomal Segmental Duplication Drives Translocation and Loss Ofp. Falciparumhistidine-Rich Protein 3

ABSTRACTMost malaria rapid diagnostic tests (RDTs) detectPlasmodium falciparumhistidine-rich protein 2 (PfHRP2) and PfHRP3, but deletions ofpfhrp2andphfrp3genes make parasites undetectable by RDTs. To better understand these deletions, we analyzed 19,289 public whole-genome-sequencedP. falciparumfield samples.Pfhrp2deletion only occurred by chromosomal breakage with subsequent telomere healing.Pfhrp3deletions involved loss frompfhrp3to the telomere and showed 3 patterns: no other associated rearrangement with evidence of telomere healing at breakpoint (Asia; Pattern 13-); 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 to each other. 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.