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Experimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasites

2010-09-16Artigo científico Acesso aberto
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dc.contributor.authorHunt, Paul
dc.contributor.authorMartinelli, Axel
dc.contributor.authorModrzynska, Katarzyna
dc.contributor.authorBorges, Sofia
dc.contributor.authorCreasey, Alison
dc.contributor.authorRodrigues, Louise
dc.contributor.authorBeraldi, Dario
dc.contributor.authorLoewe, Laurence
dc.contributor.authorFawcett, Richard
dc.contributor.authorKumar, Sujai
dc.contributor.authorThomson, Marian
dc.contributor.authorTrivedi, Urmi
dc.contributor.authorOtto, Thomas D.
dc.contributor.authorPain, Arnab
dc.contributor.authorBlaxter, Mark
dc.contributor.authorCravo, Pedro
dc.contributor.institutionInstituto de Higiene e Medicina Tropical (IHMT)
dc.contributor.institutionCentro de Malária e outras Doenças Tropicais (CMDT)
dc.contributor.pblBioMed Central (BMC)
dc.date.accessioned2021-05-06T22:43:18Z
dc.date.available2021-05-06T22:43:18Z
dc.date.issued2010-09-16
dc.description.abstractBackground: 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.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent1593068
dc.identifier.doi10.1186/1471-2164-11-499
dc.identifier.issn1471-2164
dc.identifier.otherPURE: 26056111
dc.identifier.otherPURE UUID: d5bd3831-0815-43c6-930c-42b77d706688
dc.identifier.otherScopus: 77956563692
dc.identifier.otherPubMed: 20846421
dc.identifier.otherWOS: 000282791300003
dc.identifier.otherORCID: /0000-0003-1675-4504/work/82485971
dc.identifier.urihttp://hdl.handle.net/10362/117258
dc.identifier.urlhttps://www.scopus.com/pages/publications/77956563692
dc.language.isoeng
dc.peerreviewedyes
dc.subjectGenetics
dc.subjectParasitology
dc.subjectInfectious Diseases
dc.subjectSDG 3 - Good Health and Well-being
dc.titleExperimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasitesen
dc.typejournal article
degois.publication.issue1
degois.publication.titleBMC Genomics
degois.publication.volume11
dspace.entity.typePublication
rcaap.rightsopenAccess

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