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Article ; Online: Elucidating relationships between P.falciparum prevalence and measures of genetic diversity with a combined genetic-epidemiological model of malaria.

Jason A Hendry / Dominic Kwiatkowski / Gil McVean

PLoS Computational Biology, Vol 17, Iss 8, p e

2021 Volume 1009287

Abstract: There is an abundance of malaria genetic data being collected from the field, yet using these data to understand the drivers of regional epidemiology remains a challenge. A key issue is the lack of models that relate parasite genetic diversity to ... ...

Abstract	There is an abundance of malaria genetic data being collected from the field, yet using these data to understand the drivers of regional epidemiology remains a challenge. A key issue is the lack of models that relate parasite genetic diversity to epidemiological parameters. Classical models in population genetics characterize changes in genetic diversity in relation to demographic parameters, but fail to account for the unique features of the malaria life cycle. In contrast, epidemiological models, such as the Ross-Macdonald model, capture malaria transmission dynamics but do not consider genetics. Here, we have developed an integrated model encompassing both parasite evolution and regional epidemiology. We achieve this by combining the Ross-Macdonald model with an intra-host continuous-time Moran model, thus explicitly representing the evolution of individual parasite genomes in a traditional epidemiological framework. Implemented as a stochastic simulation, we use the model to explore relationships between measures of parasite genetic diversity and parasite prevalence, a widely-used metric of transmission intensity. First, we explore how varying parasite prevalence influences genetic diversity at equilibrium. We find that multiple genetic diversity statistics are correlated with prevalence, but the strength of the relationships depends on whether variation in prevalence is driven by host- or vector-related factors. Next, we assess the responsiveness of a variety of statistics to malaria control interventions, finding that those related to mixed infections respond quickly (∼months) whereas other statistics, such as nucleotide diversity, may take decades to respond. These findings provide insights into the opportunities and challenges associated with using genetic data to monitor malaria epidemiology.
Keywords	Biology (General) ; QH301-705.5
Subject code	310
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Temporal evolution of sulfadoxine-pyrimethamine resistance genotypes and genetic diversity in response to a decade of increased interventions against Plasmodium falciparum in northern Ghana

Lucas N. Amenga-Etego / Victor Asoala / Godfred Agongo / Christopher Jacob / Sonia Goncalves / Gordon A. Awandare / Kirk A. Rockett / Dominic Kwiatkowski

Malaria Journal, Vol 20, Iss 1, Pp 1-

2021 Volume 11

Abstract: Abstract Background Anti-malarial drug resistance remains a key concern for the global fight against malaria. In Ghana sulfadoxine-pyrimethamine (SP) is used for intermittent preventive treatment of malaria in pregnancy and combined with amodiaquine for ... ...

Abstract	Abstract Background Anti-malarial drug resistance remains a key concern for the global fight against malaria. In Ghana sulfadoxine-pyrimethamine (SP) is used for intermittent preventive treatment of malaria in pregnancy and combined with amodiaquine for Seasonal Malaria Chemoprevention (SMC) during the high malaria season. Thus, surveillance of molecular markers of SP resistance is important to guide decision-making for these interventions in Ghana. Methods A total of 4469 samples from uncomplicated malaria patients collected from 2009 to 2018 was submitted to the Wellcome Trust Sanger Institute, UK for DNA sequencing using MiSeq. Genotypes were successfully translated into haplotypes in 2694 and 846 mono infections respectively for pfdhfr and pfdhps genes and the combined pfhdfr/pfdhps genes across all years. Results At the pfdhfr locus, a consistently high (> 60%) prevalence of parasites carrying triple mutants (IRNI) were detected from 2009 to 2018. Two double mutant haplotypes (NRNI and ICNI) were found, with haplotype NRNI having a much higher prevalence (average 13.8%) than ICNI (average 3.2%) across all years. Six pfdhps haplotypes were detected. Of these, prevalence of five fluctuated in a downward trend over time from 2009 to 2018, except a pfdhps double mutant (AGKAA), which increased consistently from 2.5% in 2009 to 78.2% in 2018. Across both genes, pfdhfr/pfdhps combined triple (NRNI + AAKAA) mutants were only detected in 2009, 2014, 2015 and 2018, prevalence of which fluctuated between 3.5 and 5.5%. The combined quadruple (IRNI + AAKAA) genotype increased in prevalence from 19.3% in 2009 to 87.5% in 2011 before fluctuating downwards to 19.6% in 2018 with an average prevalence of 37.4% within the nine years. Prevalence of parasites carrying the quintuple (IRNI + AGKAA or SGEAA) mutant haplotypes, which are highly refractory to SP increased over time from 14.0% in 2009 to 89.0% in 2016 before decreasing to 78.9 and 76.6% in 2017 and 2018 respectively. Though quintuple mutants are rising in ...
Keywords	Malaria ; SP resistance ; Genotypes ; Haplotype ; Pfdhfr ; Pfdhps ; Arctic medicine. Tropical medicine ; RC955-962 ; Infectious and parasitic diseases ; RC109-216
Subject code	616
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Population genomics reveal distinct and diverging populations of An. minimus in Cambodia

Brandyce St. Laurent / Nick Harding / Nick Deason / Kolthida Oy / Chea Sok Loeun / Men Sary / Rous Sunly / Sen Nhep / Eleanor Drury / Kirk Rockett / Siv Sovannaroth / Sonia Goncalves / Dominic Kwiatkowski / Alistair Miles

Communications Biology, Vol 5, Iss 1, Pp 1-

2022 Volume 10

Abstract: Using whole genome sequencing and broad sampling across the nation, the genetic diversity of the malaria mosquito An. minimus across Cambodia is described. ...

Abstract	Using whole genome sequencing and broad sampling across the nation, the genetic diversity of the malaria mosquito An. minimus across Cambodia is described.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Global diversity and balancing selection of 23 leading Plasmodium falciparum candidate vaccine antigens.

Myo T Naung / Elijah Martin / Jacob Munro / Somya Mehra / Andrew J Guy / Moses Laman / G L Abby Harrison / Livingstone Tavul / Manuel Hetzel / Dominic Kwiatkowski / Ivo Mueller / Melanie Bahlo / Alyssa E Barry

PLoS Computational Biology, Vol 18, Iss 2, p e

2022 Volume 1009801

Abstract: Investigation of the diversity of malaria parasite antigens can help prioritize and validate them as vaccine candidates and identify the most common variants for inclusion in vaccine formulations. Studies of vaccine candidates of the most virulent human ... ...

Abstract	Investigation of the diversity of malaria parasite antigens can help prioritize and validate them as vaccine candidates and identify the most common variants for inclusion in vaccine formulations. Studies of vaccine candidates of the most virulent human malaria parasite, Plasmodium falciparum, have focused on a handful of well-known antigens, while several others have never been studied. Here we examine the global diversity and population structure of leading vaccine candidate antigens of P. falciparum using the MalariaGEN Pf3K (version 5.1) resource, comprising more than 2600 genomes from 15 malaria endemic countries. A stringent variant calling pipeline was used to extract high quality antigen gene 'haplotypes' from the global dataset and a new R-package named VaxPack was used to streamline population genetic analyses. In addition, a newly developed algorithm that enables spatial averaging of selection pressure on 3D protein structures was applied to the dataset. We analysed the genes encoding 23 leading and novel candidate malaria vaccine antigens including csp, trap, eba175, ama1, rh5, and CelTOS. Our analysis shows that current malaria vaccine formulations are based on rare haplotypes and thus may have limited efficacy against natural parasite populations. High levels of diversity with evidence of balancing selection was detected for most of the erythrocytic and pre-erythrocytic antigens. Measures of natural selection were then mapped to 3D protein structures to predict targets of functional antibodies. For some antigens, geographical variation in the intensity and distribution of these signals on the 3D structure suggests adaptation to different human host or mosquito vector populations. This study provides an essential framework for the diversity of P. falciparum antigens to be considered in the design of the next generation of malaria vaccines.
Keywords	Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Investigating the drivers of the spatio-temporal patterns of genetic differences between Plasmodium falciparum malaria infections in Kilifi County, Kenya

Josephine Malinga / Polycarp Mogeni / Irene Omedo / Kirk Rockett / Christina Hubbart / Anne Jeffreys / Tom Williams / Dominic Kwiatkowski / Philip Bejon / Amanda Ross

Scientific Reports, Vol 9, Iss 1, Pp 1-

2019 Volume 13

Abstract: Abstract Knowledge of how malaria infections spread locally is important both for the design of targeted interventions aiming to interrupt malaria transmission and the design of trials to assess the interventions. A previous analysis of 1602 genotyped ... ...

Abstract	Abstract Knowledge of how malaria infections spread locally is important both for the design of targeted interventions aiming to interrupt malaria transmission and the design of trials to assess the interventions. A previous analysis of 1602 genotyped Plasmodium falciparum parasites in Kilifi, Kenya collected over 12 years found an interaction between time and geographic distance: the mean number of single nucleotide polymorphism (SNP) differences was lower for pairs of infections which were both a shorter time interval and shorter geographic distance apart. We determine whether the empiric pattern could be reproduced by a simple model, and what mean geographic distances between parent and offspring infections and hypotheses about genotype-specific immunity or a limit on the number of infections would be consistent with the data. We developed an individual-based stochastic simulation model of households, people and infections. We parameterized the model for the total number of infections, and population and household density observed in Kilifi. The acquisition of new infections, mutation, recombination, geographic location and clearance were included. We fit the model to the observed numbers of SNP differences between pairs of parasite genotypes. The patterns observed in the empiric data could be reproduced. Although we cannot rule out genotype-specific immunity or a limit on the number of infections per individual, they are not necessary to account for the observed patterns. The mean geographic distance between parent and offspring malaria infections for the base model was 0.5 km (95% CI 0.3–1.5), for a distribution with 68% of distances shorter than the mean. Very short mean distances did not fit well, but mixtures of distributions were also consistent with the data. For a pathogen which undergoes meiosis in a setting with moderate transmission and a low coverage of infections, analytic methods are limited but an individual-based model can be used with genotyping data to estimate parameter values and investigate hypotheses about underlying processes.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2019-12-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Host genetic polymorphisms and serological response against malaria in a selected population in Sri Lanka

Rajika L. Dewasurendra / Anna Jeffreys / Sharmini A. Gunawardena / Naduviladath V. Chandrasekharan / Kirk Rockett / Dominic Kwiatkowski / Nadira D. Karunaweera

Malaria Journal, Vol 17, Iss 1, Pp 1-

2018 Volume 13

Abstract: Abstract Background Antibodies against the merozoite surface protein 1-19 (MSP1-19) and the apical membrane antigen 1 (AMA1) of the malaria parasite (Plasmodium vivax) are proven to be important in protection against clinical disease. Differences in the ... ...

Abstract	Abstract Background Antibodies against the merozoite surface protein 1-19 (MSP1-19) and the apical membrane antigen 1 (AMA1) of the malaria parasite (Plasmodium vivax) are proven to be important in protection against clinical disease. Differences in the production/maintenance of antibodies may be due to many factors including host genetics. This paper discusses the association of 4 anti-malarial antibodies with selected host genetic markers. Methods Blood was collected from individuals (n = 242) with a history of malaria within past 15 years for DNA and serum. ELISA was carried out for serum to determine the concentration of anti-malarial antibodies MSP1-19 and AMA1 for both vivax and falciparum malaria. 170 SNPs related to malaria were genotyped. Associations between seropositivity, antibody levels and genetic, non-genetic factors were determined. Results Age ranged 13–74 years (mean age = 40.21 years). Majority were females. Over 90% individuals possessed either one or more type(s) of anti-malarial antibodies. Five SNPs were significantly associated with seropositivity. One SNP was associated with MSP1-19_Pv(rs739718); 4 SNPs with MSP1-19_Pf (rs6874639, rs2706379, rs2706381 and rs2075820) and1 with AMA1_Pv (rs2075820). Eleven and 7 genotypes (out of 15) were significantly associated with either presence or absence of antibodies. Three SNPs were found to be significantly associated with the antibody levels viz. rs17411697 with MSP1-19_Pv, rs2227491 with AMA1_Pv and rs229587 with AMA1_Pf. Linkage of the markers in the two groups was similar, but lower LOD scores were observed in seropositives compared to seronegatives. Discussion and conclusions The study suggests that several SNPs in the human genome that exist in Sri Lankan populations are significantly associated with anti-malarial antibodies, either with generation and/or maintenance of antibodies for longer periods, which can be due to either individual polymorphisms or most probably a combined effect of the markers.
Keywords	Arctic medicine. Tropical medicine ; RC955-962 ; Infectious and parasitic diseases ; RC109-216
Subject code	616
Language	English
Publishing date	2018-12-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Author Correction

Josephine Malinga / Polycarp Mogeni / Irene Omedo / Kirk Rockett / Christina Hubbart / Anne Jeffreys / Thomas N. Williams / Dominic Kwiatkowski / Philip Bejon / Amanda Ross

Scientific Reports, Vol 10, Iss 1, Pp 1-

Investigating the drivers of the spatio-temporal patterns of genetic differences between Plasmodium falciparum malaria infections in Kilifi County, Kenya

2020 Volume 5

Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...

Abstract	An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The genome sequence of the bootlace worm, Lineus longissimus (Gunnerus, 1770) [version 1; peer review

Dominic Kwiatkowski / Mark Blaxter / Darwin Tree of Life Barcoding collective / Wellcome Sanger Institute Tree of Life programme / Wellcome Sanger Institute Scientific Operations: DNA Pipelines collective / Tree of Life Core Informatics collective / Darwin Tree of Life Consortium

Wellcome Open Research, Vol

2 approved]

2021 Volume 6

Abstract: We present a genome assembly from an individual Lineus longissimus (the bootlace worm; Nemertea; Pilidiophora; Heteronemertea; Lineidae). The genome sequence is 391 megabases in span. The majority of the assembly is scaffolded into 19 chromosomal ... ...

Abstract	We present a genome assembly from an individual Lineus longissimus (the bootlace worm; Nemertea; Pilidiophora; Heteronemertea; Lineidae). The genome sequence is 391 megabases in span. The majority of the assembly is scaffolded into 19 chromosomal pseudomolecules.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	Wellcome
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Precision identification of high-risk phenotypes and progression pathways in severe malaria without requiring longitudinal data

Iain G. Johnston / Till Hoffmann / Sam F. Greenbury / Ornella Cominetti / Muminatou Jallow / Dominic Kwiatkowski / Mauricio Barahona / Nick S. Jones / Climent Casals-Pascual

npj Digital Medicine, Vol 2, Iss 1, Pp 1-

2019 Volume 9

Abstract: Abstract More than 400,000 deaths from severe malaria (SM) are reported every year, mainly in African children. The diversity of clinical presentations associated with SM indicates important differences in disease pathogenesis that require specific ... ...

Abstract	Abstract More than 400,000 deaths from severe malaria (SM) are reported every year, mainly in African children. The diversity of clinical presentations associated with SM indicates important differences in disease pathogenesis that require specific treatment, and this clinical heterogeneity of SM remains poorly understood. Here, we apply tools from machine learning and model-based inference to harness large-scale data and dissect the heterogeneity in patterns of clinical features associated with SM in 2904 Gambian children admitted to hospital with malaria. This quantitative analysis reveals features predicting the severity of individual patient outcomes, and the dynamic pathways of SM progression, notably inferred without requiring longitudinal observations. Bayesian inference of these pathways allows us assign quantitative mortality risks to individual patients. By independently surveying expert practitioners, we show that this data-driven approach agrees with and expands the current state of knowledge on malaria progression, while simultaneously providing a data-supported framework for predicting clinical risk.
Keywords	Computer applications to medicine. Medical informatics ; R858-859.7
Subject code	310
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	Nature Publishing Group
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Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Evolutionary analysis of the most polymorphic gene family in falciparum malaria [version 1; peer review

Thomas D. Otto / Sammy A. Assefa / Ulrike Böhme / Mandy J. Sanders / Dominic Kwiatkowski / Pf3k consortium / Matt Berriman / Chris Newbold

Wellcome Open Research, Vol

1 approved, 2 approved with reservations]

2019 Volume 4

Abstract: The var gene family of the human malaria parasite Plasmodium falciparum encode proteins that are crucial determinants of both pathogenesis and immune evasion and are highly polymorphic. Here we have assembled nearly complete var gene repertoires from ... ...

Abstract	The var gene family of the human malaria parasite Plasmodium falciparum encode proteins that are crucial determinants of both pathogenesis and immune evasion and are highly polymorphic. Here we have assembled nearly complete var gene repertoires from 2398 field isolates and analysed a normalised set of 714 from across 12 countries. This therefore represents the first large scale attempt to catalogue the worldwide distribution of var gene sequences We confirm the extreme polymorphism of this gene family but also demonstrate an unexpected level of sequence sharing both within and between continents. We show that this is likely due to both the remnants of selective sweeps as well as a worrying degree of recent gene flow across continents with implications for the spread of drug resistance. We also address the evolution of the var repertoire with respect to the ancestral genes within the Laverania and show that diversity generated by recombination is concentrated in a number of hotspots. An analysis of the subdomain structure indicates that some existing definitions may need to be revised From the analysis of this data, we can now understand the way in which the family has evolved and how the diversity is continuously being generated. Finally, we demonstrate that because the genes are distributed across the genome, sequence sharing between genotypes acts as a useful population genetic marker.
Keywords	Medicine ; R ; Science ; Q
Subject code	572
Language	English
Publishing date	2019-12-01T00:00:00Z
Publisher	Wellcome
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