The Impact of Antimalarial Resistance on the Genetic Structure of<i>Plasmodium falciparum</i>in the DRC

Verity, Robert; Aydemir, Özkan; Brazeau, Nicholas F.; Watson, Oliver J; Hathaway, Nicholas J.; Mwandagalirwa, Melchior Kashamuka; Marsh, Patrick W; Thwai, Kyaw L.; Fulton, Travis; Denton, Madeline; Morgan, Andrew P.; Parr, Jonathan B.; Tumwebaze, Patrick K; Conrad, Melissa D.; Rosenthal, Phillip; Ishengoma, Deus S.; Ngondi, Jeremiah; Gutman, Julie; Mulenga, Modest; Norris, Douglas E.; Moss, William J.; Mensah, Benedicta Ayiedu; Myers-Hansen, James L; Ghansah, Anita; Tshefu, Antoinette; Ghani, Azra C; Meshnick, Steven R.; Bailey, Jeffrey A.; Juliano, Jonathan J.

doi:10.1101/656561

Cited by 11 publications

(19 citation statements)

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“…By leveraging previously conducted MIS data, which were collected at a temporally equivalent timeframe as the samples included in the present study, we were able to assess how transmission intensity correlated with COI. Previous studies, including our recent work in the Democratic Republic of the Congo, support that there is a direct relationship between these values, with higher transmission resulting in higher COI (18,37,41) . In addition, an overall decrease in average COI was observed between the samples from this study (2017) and from Tanzanian samples collected in 2015 that were genotyped in the same manner (18) , corresponding to the overall decrease in malaria transmission in Tanzania during that period (42) .…”

Section: Discussionmentioning

confidence: 61%

“…Variant calling was conducted as previously described (15,18) . Briefly, sequences were constructed by stitching together mate-pair reads, and then clustering sequences by 1) their unique molecular identifiers (UMIs) and 2) with the qluster algorithm from SeekDeep (29) .…”

Section: Methodsmentioning

confidence: 99%

“…SNPs associated with geographic regions and K subpopulations were explored using the randomForest package in R (34) (ntree=10,000, mtry=200; parameters chosen by observing the out-of-bag (OOB) error over all trees). To investigate the relationship between genetic relatedness and geographic distance (as measured by greater circle distance using district administrative center), the inbreeding_mle function of the mipanalyzer R package was used to calculate the inbreeding coefficient (F) between sample pairs (18) . In order to avoid artificially high inbreeding coefficients for samples with high amounts of missing genotypes, this analysis only used samples with less than 50% missing genotypes.…”

Section: Population Genetic Analysesmentioning

confidence: 99%

“…Recently, molecular inversion probes (MIPs) have been adapted as assays for high-throughput characterization of Plasmodium falciparum clinical infections. These assays allow for the rapid characterization of tens to thousands of positions across the genome, and have successfully been used to track the spread of drug resistance mutations (15)(16)(17) in African countries and elucidate parasite population structure within the Democratic Republic of Congo (a high burden nation) (18) . Expanding MIPs to explore these trends in other high transmission settings in Africa is an efficient way to establish contemporary genetic trends, and can provide ongoing surveillance of circulating parasite populations.…”

Section: Introductionmentioning

confidence: 99%

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Describing the current status ofPlasmodium falciparumpopulation structure and drug resistance within mainland Tanzania using molecular inversion probes

Moser

Madebe

Aydemir

et al. 2020

Preprint

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Word Count : 246 Main Text Word Count: 3,649ABSTRACT High-throughput Plasmodium genomic data is increasingly useful in assessing prevalence of clinically important mutations and malaria transmission patterns. Understanding parasite diversity is important for identification of specific human or parasite populations that can be targeted by control programs, and to monitor the spread of mutations associated with drug resistance. An up-to-date understanding of regional parasite population dynamics is also critical to monitor the impact of control efforts. However, this data is largely absent from high-burden nations in Africa, and to date, no such analysis has been conducted for malaria parasites in Tanzania country-wide. To this end, over 1,000 P. falciparum clinical isolates were collected in 2017 from 13 sites in seven administrative regions across Tanzania, and parasites were genotyped at 1,800 variable positions genome-wide using molecular inversion probes. Population structure was detectable among Tanzanian P. falciparum parasites, roughly separating parasites from the northern and southern districts and identifying genetically admixed populations in the north. Isolates from geographically close districts were more likely to be genetically related compared to parasites sampled from more distant districts. Known drug resistance mutations were seen at increased frequency in northern districts, and additional variants with undetermined significance for antimalarial resistance also varied by geography. Malaria Indicator Survey (2017) data corresponded with genetic findings, including average region-level complexity-of-infection and malaria prevalence estimates. The parasite populations identified here provide important information on extant spatial patterns of genetic diversity of Tanzanian parasites, to which future surveys of genetic relatedness can be compared. 4 SIGNIFICANCE: Documenting dynamics of malaria parasite genomics in high-transmission settings at scale in sub-Saharan Africa is critical for policy and decision making to support ongoing malaria elimination initiatives.Using molecular inversion probes, we genotyped over 1,000 Tanzanian Plasmodium falciparum samples collected country-wide in 2017 at hundreds of variable polymorphic positions across the genome. Frequencies of known drug resistance mutations were higher in northern districts of the country compared to the south.Results also showed a distinct isolation-by-distance pattern (whereby increasing geographic distance was correlated with decreasing genetic relatedness), as well as signals of higher genetic sharing between several southern districts. These results provide, for the first time, a picture of current within-country diversity of Tanzanian P. falciparum populations.

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Section: Discussionmentioning

confidence: 61%

Section: Methodsmentioning

confidence: 99%

Section: Population Genetic Analysesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Describing the current status ofPlasmodium falciparumpopulation structure and drug resistance within mainland Tanzania using molecular inversion probes

Moser

Madebe

Aydemir

et al. 2020

Preprint

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“…Extending these methods to numerous genetically diverse loci offers the potential for high resolution comparisons of infections at a population level [17]. To this end, there have recently been efforts to multiplex large numbers of loci that reflect overall patterns of P. falciparum diversity [26,27].…”

Section: Introductionmentioning

confidence: 99%

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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Changing Prevalence of Potential Mediators of Aminoquinoline, Antifolate, and Artemisinin Resistance Across Uganda

Asua

Conrad

Aydemir

et al. 2020

The Journal of Infectious Diseases

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120

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Background In Uganda artemether-lumefantrine is recommended for malaria treatment and sulfadoxine-pyrimethamine (SP) for chemoprevention during pregnancy, but drug resistance may limit efficacies. Methods Genetic polymorphisms associated with sensitivities to key drugs were characterized in samples collected from 16 sites across Uganda in 2018 and 2019 by ligase detection reaction fluorescent microsphere, molecular inversion probe, dideoxy sequencing, and qPCR assays. Results Considering transporter polymorphisms associated with resistance to aminoquinolines, the prevalence of PfCRT 76T decreased, but varied markedly between sites (0-48% in 2018; 0-22% in 2019); additional PfCRT polymorphisms and plasmepsin-2/3 amplifications associated elsewhere with resistance to piperaquine were not seen. For PfMDR1, in 2019 the 86Y mutation was absent at all sites, the 1246Y mutation had prevalence ≤20% at 14/16 sites, and gene amplification was not seen. Considering mutations associated with high level SP resistance, prevalences of PfDHFR 164L (up to 80%) and PfDHPS 581G (up to 67%) were high at multiple sites. Considering PfK13 propeller domain mutations associated with artemisinin delayed clearance, prevalence of the 469Y and 675V mutations has increased at multiple sites in northern Uganda (up to 23% and 40%, respectively). Conclusions We demonstrate concerning spread of mutations that may limit efficacies of key antimalarial drugs.

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The Impact of Antimalarial Resistance on the Genetic Structure ofPlasmodium falciparumin the DRC

Cited by 11 publications

References 39 publications

Describing the current status ofPlasmodium falciparumpopulation structure and drug resistance within mainland Tanzania using molecular inversion probes

Describing the current status ofPlasmodium falciparumpopulation structure and drug resistance within mainland Tanzania using molecular inversion probes

Sensitive, highly multiplexed sequencing of microhaplotypes from thePlasmodium falciparumheterozygome

Changing Prevalence of Potential Mediators of Aminoquinoline, Antifolate, and Artemisinin Resistance Across Uganda

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