Resolving drug selection and migration in an inbred South American Plasmodium falciparum population with identity-by-descent analysis

Manuela Carrasquilla; Angela M. Early; Aimee R. Taylor; Angélica Knudson Ospina; Diego F. Echeverry; Timothy J.C. Anderson; Elvira Mancilla; Samanda Aponte; Pablo Cárdenas; Caroline O. Buckee; Julian C. Rayner; Fabián E. Sáenz; Daniel E. Neafsey; Vladimir Corredor

doi:10.1371/journal.ppat.1010993

Resolving drug selection and migration in an inbred South American Plasmodium falciparum population with identity-by-descent analysis

Manuela Carrasquilla^*, Angela M. Early^*, Aimee R. Taylor, Angélica Knudson Ospina, Diego F. Echeverry, Timothy J.C. Anderson, Elvira Mancilla, Samanda Aponte, Pablo Cárdenas, Caroline O. Buckee, Julian C. Rayner, Fabián E. Sáenz, Daniel E. Neafsey^*, Vladimir Corredor^*

^*Corresponding author for this work

Faculty of Exact and Natural Sciences

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

The human malaria parasite Plasmodium falciparum is globally widespread, but its prevalence varies significantly between and even within countries. Most population genetic studies in P. falciparum focus on regions of high transmission where parasite populations are large and genetically diverse, such as sub-Saharan Africa. Understanding population dynamics in low transmission settings, however, is of particular importance as these are often where drug resistance first evolves. Here, we use the Pacific Coast of Colombia and Ecuador as a model for understanding the population structure and evolution of Plasmodium parasites in small populations harboring less genetic diversity. The combination of low transmission and a high proportion of monoclonal infections means there are few outcrossing events and clonal lineages persist for long periods of time. Yet despite this, the population is evolutionarily labile and has successfully adapted to changes in drug regime. Using newly sequenced whole genomes, we measure relatedness between 166 parasites, calculated as identity by descent (IBD), and find 17 distinct but highly related clonal lineages, six of which have persisted in the region for at least a decade. This inbred population structure is captured in more detail with IBD than other common population structure analyses like PCA, ADMIXTURE, and distance-based trees. We additionally use patterns of intra-chromosomal IBD and an analysis of haplotypic variation to explore past selection events in the region. Two genes associated with chloroquine resistance, crt and aat1, show evidence of hard selective sweeps, while selection appears soft and/or incomplete at three other key resistance loci (dhps, mdr1, and dhfr). Overall, this work highlights the strength of IBD analyses for studying parasite population structure and resistance evolution in regions of low transmission, and emphasizes that drug resistance can evolve and spread in small populations, as will occur in any region nearing malaria elimination.

Original language	English
Article number	e1010993
Journal	PLoS Pathogens
Volume	18
Issue number	12
DOIs	https://doi.org/10.1371/journal.ppat.1010993
State	Published - 21 Dec 2022

Bibliographical note

Publisher Copyright:
© 2022 Carrasquilla et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding

The work performed in Colombia was supported by the Newton Caldas Fund Institutional Links G1854 Award to JCR and VC. The Medical Faculty at Universidad Nacional de Colombia provided support with awards HERMES 35988 and 32309 to VC. Whole genome sequencing of all samples obtained in Guapi was financially supported by MalariaGEN and the Wellcome Trust (206194, 090770). Financial support for Ecuador was provided by Pontificia Universidad Católica del Ecuador, grants M13416, N13416 and O13087 to FES and Ministerio de Salud Pública del Ecuador. This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Department of Health and Human Services, under Grant Number U19AI110818 to the Broad Institute awarded to DEN. TA is supported by 5R37 AI048071 from NIAID. In all cases, the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. From Colombia we thank the Guapi communities, the Secretaría Municipal de Salud del Cauca and Secretaría Departamental de Salud del Cauca. As well as the VeuPathDB outreach team for assistance in the GoldenGate decoding SNP process, with the Colombian samples. We thank Marco Galardini for bioinformatics support and helpful comments. In particular, we thank the communities in Esmeraldas and San Lorenzo and the Health districts (especially Drs. Javier Obando, César Diaz and Julio Valencia).

Funders	Funder number
Marco Galardini
Ministerio de Salud Pública del Ecuador
Newton Caldas Fund
Secretaría Departamental de Salud del Cauca
Secretaría Municipal de Salud del Cauca
National Institutes of Health
U.S. Department of Health and Human Services
National Institute of Allergy and Infectious Diseases	U19AI110818
Wellcome Trust	206194, 090770
Broad Institute	5R37 AI048071
Universidad Nacional de Colombia	35988, 32309
Pontifical Catholic University of Ecuador	M13416, O13087, N13416

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.ppat.1010993

Cite this

Carrasquilla, M., Early, A. M., Taylor, A. R., Ospina, A. K., Echeverry, D. F., Anderson, T. J. C., Mancilla, E., Aponte, S., Cárdenas, P., Buckee, C. O., Rayner, J. C., Sáenz, F. E., Neafsey, D. E., & Corredor, V. (2022). Resolving drug selection and migration in an inbred South American Plasmodium falciparum population with identity-by-descent analysis. PLoS Pathogens, 18(12), Article e1010993. https://doi.org/10.1371/journal.ppat.1010993

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title = "Resolving drug selection and migration in an inbred South American Plasmodium falciparum population with identity-by-descent analysis",

abstract = "The human malaria parasite Plasmodium falciparum is globally widespread, but its prevalence varies significantly between and even within countries. Most population genetic studies in P. falciparum focus on regions of high transmission where parasite populations are large and genetically diverse, such as sub-Saharan Africa. Understanding population dynamics in low transmission settings, however, is of particular importance as these are often where drug resistance first evolves. Here, we use the Pacific Coast of Colombia and Ecuador as a model for understanding the population structure and evolution of Plasmodium parasites in small populations harboring less genetic diversity. The combination of low transmission and a high proportion of monoclonal infections means there are few outcrossing events and clonal lineages persist for long periods of time. Yet despite this, the population is evolutionarily labile and has successfully adapted to changes in drug regime. Using newly sequenced whole genomes, we measure relatedness between 166 parasites, calculated as identity by descent (IBD), and find 17 distinct but highly related clonal lineages, six of which have persisted in the region for at least a decade. This inbred population structure is captured in more detail with IBD than other common population structure analyses like PCA, ADMIXTURE, and distance-based trees. We additionally use patterns of intra-chromosomal IBD and an analysis of haplotypic variation to explore past selection events in the region. Two genes associated with chloroquine resistance, crt and aat1, show evidence of hard selective sweeps, while selection appears soft and/or incomplete at three other key resistance loci (dhps, mdr1, and dhfr). Overall, this work highlights the strength of IBD analyses for studying parasite population structure and resistance evolution in regions of low transmission, and emphasizes that drug resistance can evolve and spread in small populations, as will occur in any region nearing malaria elimination.",

author = "Manuela Carrasquilla and Early, {Angela M.} and Taylor, {Aimee R.} and Ospina, {Ang{\'e}lica Knudson} and Echeverry, {Diego F.} and Anderson, {Timothy J.C.} and Elvira Mancilla and Samanda Aponte and Pablo C{\'a}rdenas and Buckee, {Caroline O.} and Rayner, {Julian C.} and S{\'a}enz, {Fabi{\'a}n E.} and Neafsey, {Daniel E.} and Vladimir Corredor",

note = "Publisher Copyright: {\textcopyright} 2022 Carrasquilla et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

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Carrasquilla, M, Early, AM, Taylor, AR, Ospina, AK, Echeverry, DF, Anderson, TJC, Mancilla, E, Aponte, S, Cárdenas, P, Buckee, CO, Rayner, JC, Sáenz, FE, Neafsey, DE & Corredor, V 2022, 'Resolving drug selection and migration in an inbred South American Plasmodium falciparum population with identity-by-descent analysis', PLoS Pathogens, vol. 18, no. 12, e1010993. https://doi.org/10.1371/journal.ppat.1010993

TY - JOUR

T1 - Resolving drug selection and migration in an inbred South American Plasmodium falciparum population with identity-by-descent analysis

AU - Carrasquilla, Manuela

AU - Early, Angela M.

AU - Taylor, Aimee R.

AU - Ospina, Angélica Knudson

AU - Echeverry, Diego F.

AU - Anderson, Timothy J.C.

AU - Mancilla, Elvira

AU - Aponte, Samanda

AU - Cárdenas, Pablo

AU - Buckee, Caroline O.

AU - Rayner, Julian C.

AU - Sáenz, Fabián E.

AU - Neafsey, Daniel E.

AU - Corredor, Vladimir

N1 - Publisher Copyright: © 2022 Carrasquilla et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2022/12/21

Y1 - 2022/12/21

N2 - The human malaria parasite Plasmodium falciparum is globally widespread, but its prevalence varies significantly between and even within countries. Most population genetic studies in P. falciparum focus on regions of high transmission where parasite populations are large and genetically diverse, such as sub-Saharan Africa. Understanding population dynamics in low transmission settings, however, is of particular importance as these are often where drug resistance first evolves. Here, we use the Pacific Coast of Colombia and Ecuador as a model for understanding the population structure and evolution of Plasmodium parasites in small populations harboring less genetic diversity. The combination of low transmission and a high proportion of monoclonal infections means there are few outcrossing events and clonal lineages persist for long periods of time. Yet despite this, the population is evolutionarily labile and has successfully adapted to changes in drug regime. Using newly sequenced whole genomes, we measure relatedness between 166 parasites, calculated as identity by descent (IBD), and find 17 distinct but highly related clonal lineages, six of which have persisted in the region for at least a decade. This inbred population structure is captured in more detail with IBD than other common population structure analyses like PCA, ADMIXTURE, and distance-based trees. We additionally use patterns of intra-chromosomal IBD and an analysis of haplotypic variation to explore past selection events in the region. Two genes associated with chloroquine resistance, crt and aat1, show evidence of hard selective sweeps, while selection appears soft and/or incomplete at three other key resistance loci (dhps, mdr1, and dhfr). Overall, this work highlights the strength of IBD analyses for studying parasite population structure and resistance evolution in regions of low transmission, and emphasizes that drug resistance can evolve and spread in small populations, as will occur in any region nearing malaria elimination.

AB - The human malaria parasite Plasmodium falciparum is globally widespread, but its prevalence varies significantly between and even within countries. Most population genetic studies in P. falciparum focus on regions of high transmission where parasite populations are large and genetically diverse, such as sub-Saharan Africa. Understanding population dynamics in low transmission settings, however, is of particular importance as these are often where drug resistance first evolves. Here, we use the Pacific Coast of Colombia and Ecuador as a model for understanding the population structure and evolution of Plasmodium parasites in small populations harboring less genetic diversity. The combination of low transmission and a high proportion of monoclonal infections means there are few outcrossing events and clonal lineages persist for long periods of time. Yet despite this, the population is evolutionarily labile and has successfully adapted to changes in drug regime. Using newly sequenced whole genomes, we measure relatedness between 166 parasites, calculated as identity by descent (IBD), and find 17 distinct but highly related clonal lineages, six of which have persisted in the region for at least a decade. This inbred population structure is captured in more detail with IBD than other common population structure analyses like PCA, ADMIXTURE, and distance-based trees. We additionally use patterns of intra-chromosomal IBD and an analysis of haplotypic variation to explore past selection events in the region. Two genes associated with chloroquine resistance, crt and aat1, show evidence of hard selective sweeps, while selection appears soft and/or incomplete at three other key resistance loci (dhps, mdr1, and dhfr). Overall, this work highlights the strength of IBD analyses for studying parasite population structure and resistance evolution in regions of low transmission, and emphasizes that drug resistance can evolve and spread in small populations, as will occur in any region nearing malaria elimination.

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Resolving drug selection and migration in an inbred South American Plasmodium falciparum population with identity-by-descent analysis

Abstract

Bibliographical note

Funding

UN SDGs

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