Interchromosomal segmental duplication drives translocation and loss of <i>P. falciparum</i> histidine-rich protein 3.

Abstract

Most malaria rapid diagnostic tests (RDTs) detect <i>Plasmodium falciparum</i> histidine-rich protein 2 (PfHRP2) and PfHRP3, but deletions of <i>pfhrp2</i> and <i>phfrp3</i> genes make parasites undetectable by RDTs. We analyzed 19,313 public whole-genome-sequenced <i>P. falciparum</i> field samples to understand these deletions better. <i>Pfhrp2</i> deletion only occurred by chromosomal breakage with subsequent telomere healing. <i>Pfhrp3</i> deletions involved loss from <i>pfhrp3</i> 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⁺⁺<i>pfhrp3 deletions</i>, and specific conditions are needed for their emergence and spread including low transmission, findings that can help refine surveillance strategies.