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

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• 作者：Katarzyna Kinga Modrzynska (1) (8)
  Alison Creasey (1)
  Laurence Loewe (2)
  Timothee Cezard (3)
  Sofia Trindade Borges (4) (9)
  Axel Martinelli (5)
  Louise Rodrigues (10) (5)
  Pedro Cravo (11) (5)
  Mark Blaxter (3) (6)
  Richard Carter (1)
  Paul Hunt (1) (7)
  
• 刊名：BMC Genomics
• 出版年：2012
• 出版时间：December 2012
• 年：2012
• 卷：13
• 期：1
• 全文大小：699KB
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• 作者单位：Katarzyna Kinga Modrzynska (1) (8)
  Alison Creasey (1)
  Laurence Loewe (2)
  Timothee Cezard (3)
  Sofia Trindade Borges (4) (9)
  Axel Martinelli (5)
  Louise Rodrigues (10) (5)
  Pedro Cravo (11) (5)
  Mark Blaxter (3) (6)
  Richard Carter (1)
  Paul Hunt (1) (7)
  
  1. Institute for Immunology and Infection Research, University of Edinburgh, Edinburgh, UK
  8. The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
  2. Laboratory of Genetics and Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, USA
  3. The GenePool, University of Edinburgh, Edinburgh, UK
  4. Centro de Malaria e Outras Doen莽as Tropicais/IHMT/UEI Malaria, Lisbon, Portugal
  9. Research Unit and Cardiology department, Funchal Hospital Center, Funchal, Madeira, Portugal
  5. Centro de Malaria e Outras Doen莽as Tropicais/IHMT/UEI Biologia Molecular, Lisbon, Portugal
  10. Microbiology, Molecular Genetics and Immunology, Kansas University Medical Center, Kansas City, USA
  11. IPTSP, Universidade Federal de Goi谩s, Goi芒nia, Brasil
  6. Institute for Evolutionary Biology, University of Edinburgh, Edinburgh, UK
  7. Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, UK
  

文摘

Background 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.