Estimating Relatedness Between Malaria Parasites

Taylor, Aimee R; Jacob, Pierre; Neafsey, Daniel E.; Buckee, Caroline O.

doi:10.1534/genetics.119.302120

Cited by 63 publications

(111 citation statements)

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“…Measuring genetic relatedness between malaria infections is a fundamental step towards translating genomic data into operationally relevant information on transmission dynamics and tracking parasite flow [10,44,45]. The utility of genetic data in evaluating relatedness is largely driven by the diversity of the markers used, with greater diversity generally giving better resolution.…”

Section: Discussionmentioning

confidence: 99%

“…When comparing individual parasites to each other, a sufficient number (e.g. a few hundred) of moderately diverse SNPs can theoretically provide sufficient resolution for comparisons, because combinations of many SNPs occurring within an individual parasite may be informative [44]. In practice, the ability of SNP panels to measure meaningful differences in relatedness is limited in many settings because a large proportion of infections are polyclonal, reducing the multiplicative benefit of numerous markers since phased combinations belonging to individual parasites are not directly observed.…”

Section: Discussionmentioning

confidence: 99%

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Sensitive, highly multiplexed sequencing of microhaplotypes from thePlasmodium falciparumheterozygome

Tessema¹,

Hathaway

Teyssier³

et al. 2020

Preprint

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The first two authors contributed equally to this work. ✝ The last two authors contributed equally to this work. AbstractBackground: Targeted 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. Methods:A 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.Results: Using 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/µL). In silico analyses revealed that microhaplotypes provided much higher resolution to discriminate related from unrelated polyclonal infections than biallelic SNP barcodes. Discussion:The 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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sensitive, highly multiplexed sequencing of microhaplotypes from thePlasmodium falciparumheterozygome

Tessema¹,

Hathaway

Teyssier³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…However, the validity of the 65-SNP barcode was lower in Cambodia and Vietnam, a likely reflection of the porous border between these two countries. Although the 50- and 51-SNP panels achieved better resolution in these areas, characterization of parasite transmission across borders with high levels of gene flow may be addressed better by the addition of markers suited to an analysis of identity-by-descent 22 . The application and wider validation of the 65-SNP barcode is underway, with amplicon-based sequencing assays already established for the 37 Broad barcode SNPs, and under development for the 28 new markers.…”

Section: Discussionmentioning

confidence: 99%

A molecular barcode and online tool to identify and map imported infection with Plasmodium vivax

Trimarsanto

Amato

Pearson

et al. 2019

Preprint

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Imported cases present a considerable challenge to the elimination of malaria. Traditionally, patient travel history has been used to identify imported cases, but the long-latency liver stages confound this approach in Plasmodium vivax. Molecular tools to identify and map imported cases offer a more robust approach, that can be combined with drug resistance and other surveillance markers in high-throughput, population-based genotyping frameworks. Using a machine learning approach incorporating hierarchical FST (HFST) and decision tree (DT) analysis applied to 831 P. vivax genomes from 20 countries, we identified a 28-Single Nucleotide Polymorphism (SNP) barcode with high capacity to predict the country of origin. The Matthews correlation coefficient (MCC), which provides a measure of the quality of the classifications, ranging from −1 (total disagreement) to 1 (perfect prediction), exceeded 0.9 in 15 countries in cross-validation evaluations. When combined with an existing 37-SNP P. vivax barcode, the 65-SNP panel exhibits MCC scores exceeding 0.9 in 17 countries with up to 30% missing data. As a secondary objective, several genes were identified with moderate MCC scores (median MCC range from 0.54-0.68), amenable as markers for rapid testing using low-throughput genotyping approaches. A likelihood-based classifier framework was established, that supports analysis of missing data and polyclonal infections. To facilitate investigator-lead analyses, the likelihood framework is provided as a web-based, open-access platform (vivaxGEN-geo) to support the analysis and interpretation of data produced either at the 28-SNP core or full 65-SNP barcode. These tools can be used by malaria control programs to identify the main reservoirs of infection so that resources can be focused to where they are needed most.

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“…The results were highly informative: the vast majority of successfully genotyped P. falciparum samples were deemed monoclonal (325 of 400) with a strong association between clonality and incidence. Among the 325 monoclonal samples, 136 unique haploid multilocus genotypes (MLGs) were identified using relatedness based on identity-by-state (IBS), which is a correlate of IBD [25] (and has been used elsewhere to characterise connectivity between nearby malaria parasite populations [12–14]). Of the 136 MLGs, 44 infected two or more patients (max.…”

Section: Introductionmentioning

confidence: 99%

“…[5]), highly-related parasites were classified using a threshold; however, confidence intervals allow uncertainty to be accounted for. This is important because relatedness estimated using limited genotype data can be overwhelmed by uncertainty [25]. Our approach includes two additional contributions.…”

Section: Introductionmentioning

confidence: 99%

Identity-by-descent relatedness estimates with uncertainty characterise departure from isolation-by-distance betweenPlasmodium falciparumpopulations on the Colombian-Pacific coast

Taylor

Echeverry

Anderson

et al. 2020

Preprint

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18Characterising connectivity between geographically separated biological populations is a common goal in 19 many fields. Recent approaches to understanding connectivity between malaria parasite populations, with 20 implications for disease control efforts, have used estimates of relatedness based on identity-by-descent (IBD). 21 However, uncertainty around estimated relatedness has not been accounted for to date. IBD-based relat-22 edness estimates with uncertainty were computed for pairs of monoclonal Plasmodium falciparum samples 23 collected from five cities on the Colombian-Pacific coast where long-term clonal propagation of P. falciparum 24 is frequent. The cities include two official ports, Buenaventura and Tumaco, that are separated geographically 25 but connected by frequent marine traffic. The fraction of highly-related sample pairs (whose classification 26 accounts for uncertainty) was greater within cities versus between. However, based on both the fraction 27 of highly-related sample pairs and on a threshold-free approach (Wasserstein distances between parasite 28 populations) connectivity between Buenaventura and Tumaco was disproportionally high. Buenaventura- 29Tumaco connectivity was consistent with three separate transmission events involving parasites from five 30 different clonal components (groups of statistically indistinguishable parasites identified under a graph theo-31 retic framework). To conclude, P. falciparum population connectivity on the Colombian-Pacific coast abides 32 by accessibility not isolation-by-distance, potentially implicating marine traffic in malaria transmission with 33 opportunities for targeted intervention. Further investigations are required to test this and alternative hy-34 potheses. For the first time in malaria epidemiology, we account for uncertainty around estimated relatedness 35 (an important consideration for future studies that plan to use genotype versus whole genome sequence data 36 to estimate IBD-based relatedness); we also use a threshold-free approach to compare parasite populations, 37 and identify clonal components in a statistically principled manner. The approaches we employ could be 38 adapted to other recombining organisms with mixed mating systems, thus have broad relevance. 39 1 In many research fields genetic data are used to help characterise connectivity between geographically dis-41 parate biological populations, with numerous applications in conservation, agriculture, and public health. 42Patterns of genetic similarity between pathogen populations help us understand how the disease spreads. 43 Patterns of relatedness (a measure of genetic similarity) between malaria parasites in different human pop-44 ulations, for instance, help characterise the connectivity between them, thus guide the design of targeted 45 public health interventions [1]. 46 Several methods are employed to measure genetic similarity and thus characterise connectivity. Phylo-47 genetic methods, in which genetic distances between individuals are measured in unit...

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Estimating Relatedness Between Malaria Parasites

Cited by 63 publications

References 78 publications

Sensitive, highly multiplexed sequencing of microhaplotypes from thePlasmodium falciparumheterozygome

Sensitive, highly multiplexed sequencing of microhaplotypes from thePlasmodium falciparumheterozygome

A molecular barcode and online tool to identify and map imported infection with Plasmodium vivax

Identity-by-descent relatedness estimates with uncertainty characterise departure from isolation-by-distance betweenPlasmodium falciparumpopulations on the Colombian-Pacific coast

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