Lineage-informative microhaplotypes for recurrence classification and spatio-temporal surveillance of Plasmodium vivax malaria parasites

Sasha V. Siegel, Hidayat Trimarsanto, Roberto Amato, Kathryn Murie, Aimee R. Taylor, Edwin Sutanto, Mariana Kleinecke, Georgia Whitton, James A. Watson, Mallika Imwong, Ashenafi Assefa, Awab Ghulam Rahim, Hoang Chau Nguyen, Tinh Hien Tran, Justin A. Green, Gavin C. K. W. Koh, Nicholas J. White, Nicholas Day, Dominic P. Kwiatkowski, Julian C. Rayner, Ric N. Price and Sarah Auburn ()
Additional contact information
Sasha V. Siegel: Hinxton
Hidayat Trimarsanto: Menzies School of Health Research and Charles Darwin University
Roberto Amato: Hinxton
Kathryn Murie: Hinxton
Aimee R. Taylor: University de Paris, Infectious Disease Epidemiology and Analytics Unit
Edwin Sutanto: Exeins Health Initiative
Mariana Kleinecke: Menzies School of Health Research and Charles Darwin University
Georgia Whitton: Hinxton
James A. Watson: University of Oxford
Mallika Imwong: Mahidol University
Ashenafi Assefa: Ethiopian Public Health Institute
Awab Ghulam Rahim: Mahidol University
Hoang Chau Nguyen: Hospital for Tropical Diseases
Tinh Hien Tran: Hospital for Tropical Diseases
Justin A. Green: Formerly GlaxoSmithKline
Gavin C. K. W. Koh: Northwick Park Hospital
Nicholas J. White: University of Oxford
Nicholas Day: University of Oxford
Dominic P. Kwiatkowski: Hinxton
Julian C. Rayner: University of Cambridge
Ric N. Price: Menzies School of Health Research and Charles Darwin University
Sarah Auburn: Menzies School of Health Research and Charles Darwin University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Challenges in classifying recurrent Plasmodium vivax infections constrain surveillance of antimalarial efficacy and transmission. Recurrent infections may arise from activation of dormant liver stages (relapse), blood-stage treatment failure (recrudescence) or reinfection. Molecular inference of familial relatedness (identity-by-descent or IBD) can help resolve the probable origin of recurrences. As whole genome sequencing of P. vivax remains challenging, targeted genotyping methods are needed for scalability. We describe a P. vivax marker discovery framework to identify and select panels of microhaplotypes (multi-allelic markers within small, amplifiable segments of the genome) that can accurately capture IBD. We evaluate panels of 50–250 microhaplotypes discovered in a global set of 615 P. vivax genomes. A candidate global 100-microhaplotype panel exhibits high marker diversity in the Asia-Pacific, Latin America and horn of Africa (median HE = 0.70–0.81) and identifies 89% of the polyclonal infections detected with genome-wide datasets. Data simulations reveal lower error in estimating pairwise IBD using microhaplotypes relative to traditional biallelic SNP barcodes. The candidate global panel also exhibits high accuracy in predicting geographic origin and captures local infection outbreak and bottlenecking events. Our framework is open-source enabling customised microhaplotype discovery and selection, with potential for porting to other species or data resources.

Date: 2024
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DOI: 10.1038/s41467-024-51015-3

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