Logo do repositório
 
Publicação

Quantitative genome re-sequencing defines multiple mutations conferring chloroquine resistance in rodent malaria

2012-03-21Artigo científico Acesso aberto
Ver registo simples
dc.contributor.authorKinga Modrzynska, Katarzyna
dc.contributor.authorCreasey, Alison
dc.contributor.authorLoewe, Laurence
dc.contributor.authorCezard, Timothee
dc.contributor.authorTrindade Borges, Sofia
dc.contributor.authorMartinelli, Axel
dc.contributor.authorRodrigues, Louise
dc.contributor.authorCravo, Pedro
dc.contributor.authorBlaxter, Mark
dc.contributor.authorCarter, Richard
dc.contributor.authorHunt, Paul
dc.contributor.institutionCentro de Malária e outras Doenças Tropicais (CMDT)
dc.contributor.institutionInstituto de Higiene e Medicina Tropical (IHMT)
dc.contributor.pblBioMed Central (BMC)
dc.date.accessioned2021-05-05T23:24:41Z
dc.date.available2021-05-05T23:24:41Z
dc.date.issued2012-03-21
dc.description.abstractBackground: Drug resistance in the malaria parasite Plasmodium falciparum severely compromises the treatment and control of malaria. A knowledge of the critical mutations conferring resistance to particular drugs is important in understanding modes of drug action and mechanisms of resistances. They are required to design better therapies and limit drug resistance.A mutation in the gene (pfcrt) encoding a membrane transporter has been identified as a principal determinant of chloroquine resistance in P. falciparum, but we lack a full account of higher level chloroquine resistance. Furthermore, the determinants of resistance in the other major human malaria parasite, P. vivax, are not known. To address these questions, we investigated the genetic basis of chloroquine resistance in an isogenic lineage of rodent malaria parasite P. chabaudi in which high level resistance to chloroquine has been progressively selected under laboratory conditions.Results: Loci containing the critical genes were mapped by Linkage Group Selection, using a genetic cross between the high-level chloroquine-resistant mutant and a genetically distinct sensitive strain. A novel high-resolution quantitative whole-genome re-sequencing approach was used to reveal three regions of selection on chr11, chr03 and chr02 that appear progressively at increasing drug doses on three chromosomes. Whole-genome sequencing of the chloroquine-resistant parent identified just four point mutations in different genes on these chromosomes. Three mutations are located at the foci of the selection valleys and are therefore predicted to confer different levels of chloroquine resistance. The critical mutation conferring the first level of chloroquine resistance is found in aat1, a putative aminoacid transporter.Conclusions: Quantitative trait loci conferring selectable phenotypes, such as drug resistance, can be mapped directly using progressive genome-wide linkage group selection. Quantitative genome-wide short-read genome resequencing can be used to reveal these signatures of drug selection at high resolution. The identities of three genes (and mutations within them) conferring different levels of chloroquine resistance generate insights regarding the genetic architecture and mechanisms of resistance to chloroquine and other drugs. Importantly, their orthologues may now be evaluated for critical or accessory roles in chloroquine resistance in human malarias P. vivax and P. falciparum.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent1535038
dc.identifier.doi10.1186/1471-2164-13-106
dc.identifier.issn1471-2164
dc.identifier.otherPURE: 26122313
dc.identifier.otherPURE UUID: d3308048-5508-4d7a-89dd-89dd46906d89
dc.identifier.otherScopus: 84861658779
dc.identifier.otherPubMed: 22435897
dc.identifier.otherWOS: 000304567200001
dc.identifier.otherORCID: /0000-0003-1675-4504/work/82646981
dc.identifier.urihttp://hdl.handle.net/10362/117135
dc.identifier.urlhttps://www.scopus.com/pages/publications/84861658779
dc.language.isoeng
dc.peerreviewedyes
dc.subjectGenetics
dc.subjectParasitology
dc.subjectInfectious Diseases
dc.subjectSDG 3 - Good Health and Well-being
dc.titleQuantitative genome re-sequencing defines multiple mutations conferring chloroquine resistance in rodent malariaen
dc.typejournal article
degois.publication.issue1
degois.publication.titleBMC Genomics
degois.publication.volume13
dspace.entity.typePublication
rcaap.rightsopenAccess

Ficheiros

Principais
A mostrar 1 - 1 de 1
Miniatura
Nome:
Quantitative_genome_re_sequencing.pdf
Tamanho:
1.46 MB
Formato:
Adobe Portable Document Format
Ver/Abrir

Coleções

IHMT: PM - Artigos em revista internacional com arbitragem científica