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Title: Early Genomic Amplifications in Blood-Stages of ARMD Plasmodium falciparum Acquiring De Novo Drug Resistance [Genome variation]      
dateReleased:
05-01-2013
description:
While many molecular changes associated with commonly used antimalarials are known, there remain important questions on how parasites arrive at the correct causal molecular solutions in a haploid genome. We selected for resistance to DSM1, a novel dihydroorotate dehydrogenase (DHODH) inhibitor with a non-biological triazolopyrimidine scaffold, in P. falciparum with the Accelerated Resistance to Multiple Drugs (ARMD) trait. While direct sequencing revealed no mutations in the target DHODH gene, comparative genomic hybridizations from four independently selected DSM1-resistant clones showed a large, single 34-95kb amplification in each clone. Each amplified region always included the DHODH locus. The length of this region and the resulting 2- to 3-fold DHODH copy number increase were verified at the RNA and protein level. DSM1 resistance was stable over several months of in vitro culture. Additional selection at higher DSM1 concentrations caused further gains in CNVs at the DHODH locus. The present system validated DHODH as a key target of the triazolopyrimidine antimalarial, DSM1 and, more importantly, captured large, random CNVs as an early step in the initiation of drug resistance in malaria parasites. This defined system is expected to be valuable for characterizing early, causal molecular steps leading to successful drug resistance gDNA from P. falciparum DSM1 resistant cell-line was hybridized against gDNA of parental strain, Dd2. DSM1 resistant cell culture was maintained under DSM1 at 333 nM, microarray data were obtained from three hybridizations using gDNA from three independent parasite cultures
privacy:
not applicable
aggregation:
instance of dataset
ID:
E-GEOD-35732
refinement:
raw
alternateIdentifiers:
35732
keywords:
functional genomics
dateModified:
06-02-2014
availability:
available
types:
gene expression
name:
Plasmodium falciparum Dd2
ID:
A-GEOD-15221
name:
Plasmodium falciparum Rathod09A_10816
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-35732/E-GEOD-35732.raw.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ebi.ac.uk/arrayexpress/files/E-GEOD-35732/E-GEOD-35732.processed.1.zip
storedIn:
ArrayExpress
qualifier:
gzip compressed
format:
TXT
accessType:
download
authentication:
none
authorization:
none
accessURL: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE35732
storedIn:
Gene Expression Omnibus
qualifier:
not compressed
format:
HTML
accessType:
landing page
primary:
true
authentication:
none
authorization:
none
abbreviation:
EBI
homePage: http://www.ebi.ac.uk/
ID:
SCR:004727
name:
European Bioinformatics Institute
homePage: https://www.ebi.ac.uk/arrayexpress/
ID:
SCR:002964
name:
ArrayExpress

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