Biology subjects

Hathaway, N. J.

Publications and source records attributed to Hathaway, N. J..

5 recordsLinked to original sources

bioRxiv2026

Whole-genome characterization of Plasmodium falciparum population structure and drug resistance across Uganda and neighboring countries

Uganda has one of the world's highest malaria burdens, but parasite population structure and connectivity have not been characterized nationally with whole-genome data. We analyzed 249 monoclonal Plasmodium falciparum genomes from 26 sentinel sites across Uganda in 2023 and compared them with publicly available genomes from five neighboring countries. Genetic diversity was high and differentiation low in Uganda, but identity-by-descent detected limited structure. This was most pronounced in the low-transmission southwest, where parasites shared ancestry and recent relatedness with isolates from western Tanzania. Selection scans identified signals at loci associated with resistance to artemisinins and their partner drugs, and to chloroquine and antifolates. The strongest signal was at PfPX1 where the PIN haplotype (L1222P, M1701I, D1705N) reached 70% prevalence nationwide, but selection was carried by PIN haplotypes that had additionally acquired D384A, largely confined to northern and eastern Uganda. A second substitution at the same codon, D384Y, formed a haplotype shared across the Tanzanian border. PfKelch13 variants were partitioned across multiple backgrounds, consistent with repeated independent emergence, and C469Y was enriched on the PfPX1 D384A-PIN background. These genomes provide a 2023 baseline for tracking potential mediators of drug resistance and support coordinated genomic surveillance across Uganda and its neighbors.

genomics↗

bioRxiv2025

The Portable Microhaplotype Object and Tools

Structured AbstractO_ST_ABSMotivationC_ST_ABSThe rapid increase in the generation of targeted sequencing data offers immense potential for research, medicine, and public health, however the lack of an established standard for these data has led to disparate solutions for data storage. A widely accepted standard is essential for data sharing, reuse, and the coordinated development of interoperable analysis tools. ResultsWe propose the Portable Microhaplotype Object (PMO), a standardized format for efficiently and losslessly storing phased targeted sequencing data (microhaplotypes). The PMO format is JSON-based, allowing efficient, relational storage of genetic data together with relevant metadata to minimize orphaned data. The format includes required fields and a curated set of optional fields leveraging established ontologies. To facilitate ease of use, we developed pmotools-python, an open-source package for creating, manipulating, and exporting PMO data into common formats. Additionally, we provide a simple web-based app to quickly create PMO files from tabular inputs, making the format accessible to a wide variety of users. Example datasets from Plasmodium, Anopheles, Escherichia coli, and Staphylococcus aureus demonstrate the broad applicability of the approach. PMO will streamline data sharing, foster interoperability, and accelerate the development of harmonized analysis tools. Availability and implementationThe Portable Microhaplotype Object (PMO) project, including the ontology specification, software tools, example datasets, and tutorials, is freely available athttps://plasmogenepi.github.io/PMO_Docs/. Key software components and datasets have archived releases with DOIs to ensure permanence, detailed in the Supplementary Text 1-5. Contactkathrynmmurie@gmail.com or nickjhathaway@gmail.com

bioinformatics↗

bioRxiv2022

Non-allelic homologous recombination driven translocation explains histidine-rich protein 3 deletion mechanism in Plasmodium falciparum

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 3 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.

genomics↗

bioRxiv2020

Sensitive, highly multiplexed sequencing of microhaplotypes from the Plasmodium falciparum heterozygome

BackgroundTargeted next generation sequencing offers the potential for consistent, deep coverage of information rich genomic regions to characterize polyclonal Plasmodium falciparum infections. However, methods to identify and sequence these genomic regions are currently limited. MethodsA bioinformatic pipeline and multiplex methods were developed to identify and simultaneously sequence 100 targets and applied to dried blood spot (DBS) controls and field isolates from Mozambique. For comparison, WGS data were generated for the same controls. ResultsUsing publicly available genomes, 4465 high diversity genomic regions suited for targeted sequencing were identified, representing the P. falciparum heterozygome. For this study, 93 microhaplotypes with high diversity (median HE = 0.7) were selected along with 7 drug resistance loci. The sequencing method achieved very high coverage (median 99%), specificity (99.8%) and sensitivity (90% for haplotypes with 5% within sample frequency in DBS with 100 parasites/{micro}L). In silico analyses revealed that microhaplotypes provided much higher resolution to discriminate related from unrelated polyclonal infections than biallelic SNP barcodes. DiscussionThe bioinformatic and laboratory methods outlined here provide a flexible tool for efficient, low-cost, high throughput interrogation of the P. falciparum genome, and can be tailored to simultaneously address multiple questions of interest in various epidemiological settings.

molecular biology↗

bioRxiv2019

The Impact of Antimalarial Resistance on the Genetic Structure of Plasmodium falciparum in the DRC

The Democratic Republic of the Congo (DRC) harbors 11% of global malaria cases, yet little is known about the spatial and genetic structure of the parasite population in that country. We sequenced 2537 Plasmodium falciparum infections, including a nationally representative population sample from DRC and samples from surrounding countries, using molecular inversion probes - a novel high-throughput genotyping tool. We identified an east-west divide in haplotypes known to confer resistance to chloroquine and sulfadoxine-pyrimethamine. Furthermore, we identified highly related parasites over large geographic distances, indicative of gene flow and migration. Our results were consistent with a background of isolation by distance combined with the effects of selection for antimalarial drug resistance. This study provides a high-resolution view of parasite genetic structure across a large country in Africa and provides a baseline to study how implementation programs may impact parasite populations.

genomics↗