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

Detalhes bibliográficos
Autor(a) principal: Hunt, Paul
Data de Publicação: 2010
Outros Autores: Martinelli, Axel, Modrzynska, Katarzyna, Borges, Sofia, Creasey, Alison, Rodrigues, Louise, Beraldi, Dario, Loewe, Laurence, Fawcett, Richard, Kumar, Sujai, Thomson, Marian, Trivedi, Urmi, Otto, Thomas D., Pain, Arnab, Blaxter, Mark, Cravo, Pedro
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10362/117258
Resumo: 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.
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spelling Experimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasitesGeneticsParasitologyInfectious DiseasesSDG 3 - Good Health and Well-beingBackground: 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.Instituto de Higiene e Medicina Tropical (IHMT)Centro de Malária e outras Doenças Tropicais (CMDT)RUNHunt, PaulMartinelli, AxelModrzynska, KatarzynaBorges, SofiaCreasey, AlisonRodrigues, LouiseBeraldi, DarioLoewe, LaurenceFawcett, RichardKumar, SujaiThomson, MarianTrivedi, UrmiOtto, Thomas D.Pain, ArnabBlaxter, MarkCravo, Pedro2021-05-06T22:43:18Z2010-09-162010-09-16T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10362/117258eng1471-2164PURE: 26056111https://doi.org/10.1186/1471-2164-11-499info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-11T05:00:22Zoai:run.unl.pt:10362/117258Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:43:33.973392Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Experimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasites
title Experimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasites
spellingShingle Experimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasites
Hunt, Paul
Genetics
Parasitology
Infectious Diseases
SDG 3 - Good Health and Well-being
title_short Experimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasites
title_full Experimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasites
title_fullStr Experimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasites
title_full_unstemmed Experimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasites
title_sort Experimental evolution, genetic analysis and genome re-sequencing reveal the mutation conferring artemisinin resistance in an isogenic lineage of malaria parasites
author Hunt, Paul
author_facet Hunt, Paul
Martinelli, Axel
Modrzynska, Katarzyna
Borges, Sofia
Creasey, Alison
Rodrigues, Louise
Beraldi, Dario
Loewe, Laurence
Fawcett, Richard
Kumar, Sujai
Thomson, Marian
Trivedi, Urmi
Otto, Thomas D.
Pain, Arnab
Blaxter, Mark
Cravo, Pedro
author_role author
author2 Martinelli, Axel
Modrzynska, Katarzyna
Borges, Sofia
Creasey, Alison
Rodrigues, Louise
Beraldi, Dario
Loewe, Laurence
Fawcett, Richard
Kumar, Sujai
Thomson, Marian
Trivedi, Urmi
Otto, Thomas D.
Pain, Arnab
Blaxter, Mark
Cravo, Pedro
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Higiene e Medicina Tropical (IHMT)
Centro de Malária e outras Doenças Tropicais (CMDT)
RUN
dc.contributor.author.fl_str_mv Hunt, Paul
Martinelli, Axel
Modrzynska, Katarzyna
Borges, Sofia
Creasey, Alison
Rodrigues, Louise
Beraldi, Dario
Loewe, Laurence
Fawcett, Richard
Kumar, Sujai
Thomson, Marian
Trivedi, Urmi
Otto, Thomas D.
Pain, Arnab
Blaxter, Mark
Cravo, Pedro
dc.subject.por.fl_str_mv Genetics
Parasitology
Infectious Diseases
SDG 3 - Good Health and Well-being
topic Genetics
Parasitology
Infectious Diseases
SDG 3 - Good Health and Well-being
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.
publishDate 2010
dc.date.none.fl_str_mv 2010-09-16
2010-09-16T00:00:00Z
2021-05-06T22:43:18Z
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dc.identifier.uri.fl_str_mv http://hdl.handle.net/10362/117258
url http://hdl.handle.net/10362/117258
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 1471-2164
PURE: 26056111
https://doi.org/10.1186/1471-2164-11-499
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