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

View ORCID ProfileManuela Carrasquilla, View ORCID ProfileAngela M Early, View ORCID ProfileAimee R Taylor, Angélica Knudson, Diego F Echeverry, View ORCID ProfileTimothy JC Anderson, Elvira Mancilla, Samanda Aponte, Pablo Cárdenas, View ORCID ProfileCaroline O Buckee, View ORCID ProfileJulian C Rayner, Fabián E Sáenz, View ORCID ProfileDaniel E Neafsey, Vladimir Corredor
doi: https://doi.org/10.1101/2022.02.18.480973
Manuela Carrasquilla
1Department of Immunology and Infectious Disease, Harvard T.H.Chan School of Public Health, Boston, MA, USA
2Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • ORCID record for Manuela Carrasquilla
  • For correspondence: carrasquilla@mpiib-berlin.mpg.de early@broadinstitute.org neafsey@hsph.harvard.edu vcorredore@unal.edu.co
Angela M Early
1Department of Immunology and Infectious Disease, Harvard T.H.Chan School of Public Health, Boston, MA, USA
2Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • For correspondence: carrasquilla@mpiib-berlin.mpg.de early@broadinstitute.org neafsey@hsph.harvard.edu vcorredore@unal.edu.co
Aimee R Taylor
2Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
3Center for Communicable Disease Dynamics, Harvard T.H.Chan School of Public Health, Boston, MA, USA
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Angélica Knudson
4Departamento de Microbiología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, Colombia
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Diego F Echeverry
5Departamento de Microbiología, Facultad de Salud, Universidad del Valle, Cali, Colombia
6Centro Internacional de Entrenamiento e Investigaciones Médicas (CIDEIM), Cali, Colombia
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Timothy JC Anderson
7Program in Disease Intervention and Prevention, Texas Biomedical Research Institution, San Antonio, Texas
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Elvira Mancilla
8Secretaría Departamental de Salud del Cauca, Popayán, Colombia
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Samanda Aponte
9Departamento de Salud Pública, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, Colombia
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Pablo Cárdenas
10Department of Biological Engineering, Massachusetts Institute of Technology
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Caroline O Buckee
3Center for Communicable Disease Dynamics, Harvard T.H.Chan School of Public Health, Boston, MA, USA
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  • ORCID record for Caroline O Buckee
Julian C Rayner
11Wellcome Sanger Institute, Hinxton, Cambridge, UK
12Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK
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Fabián E Sáenz
13Centro de Investigación para la Salud en América Latina, Facultad de Ciencias Exactas y Naturales, Pontificia Universidad Católica del Ecuador, Quito, Ecuador
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Daniel E Neafsey
1Department of Immunology and Infectious Disease, Harvard T.H.Chan School of Public Health, Boston, MA, USA
2Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • For correspondence: carrasquilla@mpiib-berlin.mpg.de early@broadinstitute.org neafsey@hsph.harvard.edu vcorredore@unal.edu.co
Vladimir Corredor
9Departamento de Salud Pública, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, Colombia
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  • For correspondence: carrasquilla@mpiib-berlin.mpg.de early@broadinstitute.org neafsey@hsph.harvard.edu vcorredore@unal.edu.co
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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 low 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 multiple drug regimes. Using 166 newly sequenced whole genomes, we measure relatedness between 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 with 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 the role of recombination in spreading drug resistance mutations throughout 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 extremely small populations, as will occur in any region nearing malaria elimination.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://github.com/aimeertaylor/ColombianBarcode

  • https://github.com/aimeertaylor/ColombianBarcode/blob/master/Code/Extended_analysis/Analysis_summary.Rmd

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted February 19, 2022.
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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, Diego F Echeverry, Timothy JC Anderson, Elvira Mancilla, Samanda Aponte, Pablo Cárdenas, Caroline O Buckee, Julian C Rayner, Fabián E Sáenz, Daniel E Neafsey, Vladimir Corredor
bioRxiv 2022.02.18.480973; doi: https://doi.org/10.1101/2022.02.18.480973
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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, Diego F Echeverry, Timothy JC Anderson, Elvira Mancilla, Samanda Aponte, Pablo Cárdenas, Caroline O Buckee, Julian C Rayner, Fabián E Sáenz, Daniel E Neafsey, Vladimir Corredor
bioRxiv 2022.02.18.480973; doi: https://doi.org/10.1101/2022.02.18.480973

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