Interchromosomal segmental duplication drives translocation and loss of histidine-rich protein 3.

Most malaria rapid diagnostic tests (RDTs) detect histidine-rich protein 2 (PfHRP2) and PfHRP3, but deletions of and genes make parasites undetectable by RDTs. We analyzed 19,313 public whole-genome-sequenced field samples to understand these deletions better. deletion only occurred by chromosomal breakage with subsequent telomere healing. deletions involved loss from to the telomere and showed three patterns: no other associated rearrangement with evidence of telomere healing at breakpoint (Asia; Pattern 13TARE1); associated with duplication of a chromosome 5 segment containing multidrug-resistant-1 gene (Asia; Pattern 135); and most commonly, associated with duplication of a chromosome 11 segment (Americas/Africa; Pattern 1311). 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 1311 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 1311, and specific conditions are needed for their emergence and spread including low transmission, findings that can help refine surveillance strategies.