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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Experimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasites
BMC Genomics, Volume 11, No. 1, Article 499, Year 2010
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Description
Background: Classical and quantitative linkage analyses of genetic crosses have traditionally been used to map genes of interest, such as those conferring chloroquine or quinine resistance in malaria parasites. Next-generation sequencing technologies now present the possibility of determining genome-wide genetic variation at single base-pair resolution. Here, we combine in vivo experimental evolution, a rapid genetic strategy and whole genome re-sequencing to identify the precise genetic basis of artemisinin resistance in a lineage of the rodent malaria parasite, Plasmodium chabaudi. Such genetic markers will further the investigation of resistance and its control in natural infections of the human malaria, P. falciparum.Results: A lineage of isogenic in vivo drug-selected mutant P. chabaudi parasites was investigated. By measuring the artemisinin responses of these clones, the appearance of an in vivo artemisinin resistance phenotype within the lineage was defined. The underlying genetic locus was mapped to a region of chromosome 2 by Linkage Group Selection in two different genetic crosses. Whole-genome deep coverage short-read re-sequencing (Illumina®Solexa) defined the point mutations, insertions, deletions and copy-number variations arising in the lineage. Eight point mutations arise within the mutant lineage, only one of which appears on chromosome 2. This missense mutation arises contemporaneously with artemisinin resistance and maps to a gene encoding a de-ubiquitinating enzyme.Conclusions: This integrated approach facilitates the rapid identification of mutations conferring selectable phenotypes, without prior knowledge of biological and molecular mechanisms. For malaria, this model can identify candidate genes before resistant parasites are commonly observed in natural human malaria populations. © 2010 Hunt et al; licensee BioMed Central Ltd.
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https://efashare.b-cdn.net/share/pmc/articles/PMC2996995/bin/1471-2164-11-499-S1.XLS
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https://efashare.b-cdn.net/share/pmc/articles/PMC2996995/bin/1471-2164-11-499-S8.XLS
https://efashare.b-cdn.net/share/pmc/articles/PMC2996995/bin/1471-2164-11-499-S9.XLS
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https://efashare.b-cdn.net/share/pmc/articles/PMC2996995/bin/1471-2164-11-499-S11.doc
https://efashare.b-cdn.net/share/pmc/articles/PMC2996995/bin/1471-2164-11-499-S12.xls
Authors & Co-Authors
Hunt, Paul
United Kingdom, Edinburgh
The University of Edinburgh
Martinelli, Axel
United Kingdom, Edinburgh
The University of Edinburgh
Portugal, Lisbon
Instituto de Higiene e Medicina Tropical
Modrzynska, Katarzyna K.
United Kingdom, Edinburgh
The University of Edinburgh
Borges, Sofia
Portugal, Lisbon
Instituto de Higiene e Medicina Tropical
Creasey, Alison M.
United Kingdom, Edinburgh
The University of Edinburgh
Rodrigues, Louise
Portugal, Lisbon
Instituto de Higiene e Medicina Tropical
Beraldi, Dario
United Kingdom, Edinburgh
The University of Edinburgh
United Kingdom, Roslin
The Royal Dick School of Veterinary Studies
Loewe, Laurence
United Kingdom, Edinburgh
The University of Edinburgh
Fawcett, Richard
United Kingdom, Edinburgh
The University of Edinburgh
Kumar, Sujai
United Kingdom, Edinburgh
The University of Edinburgh
Thomson, Marian
United Kingdom, Edinburgh
The University of Edinburgh
Trivedi, Urmi
United Kingdom, Edinburgh
The University of Edinburgh
Otto, Thomas Dan
United Kingdom, Hinxton
Wellcome Sanger Institute
Pain, Arnab P.
United Kingdom, Hinxton
Wellcome Sanger Institute
Saudi Arabia, Thuwal
King Abdullah University of Science and Technology
Blaxter, Mark L.
United Kingdom, Edinburgh
The University of Edinburgh
Cravo, Pedro Vítor Lemos
Portugal, Lisbon
Instituto de Higiene e Medicina Tropical
Statistics
Citations: 84
Authors: 16
Affiliations: 5
Identifiers
Doi:
10.1186/1471-2164-11-499
e-ISSN:
14712164
Research Areas
Cancer
Genetics And Genomics
Health System And Policy
Infectious Diseases
Study Approach
Quantitative