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Drug-resistant genotypes and multi-clonality in Plasmodium falciparum analysed by direct genome sequencing from peripheral blood of malaria patients

Robinson, Timothy, Campino, Susana G., Auburn, Sarah, Assefa, Samuel A., Polley, Spencer D., Manske, Magnus, MacInnis, Bronwyn, Rockett, Kirk A., Maslen, Gareth L., Sanders, Mandy, Quail, Michael A., Chiodini, Peter L., Kwiatkowski, Dominic P., Clark, Taane G. and Sutherland, Colin J. (2011). Drug-resistant genotypes and multi-clonality in Plasmodium falciparum analysed by direct genome sequencing from peripheral blood of malaria patients. PLoS One,6(8):e23204.

Document type: Journal Article
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Title Drug-resistant genotypes and multi-clonality in Plasmodium falciparum analysed by direct genome sequencing from peripheral blood of malaria patients
Author Robinson, Timothy
Campino, Susana G.
Auburn, Sarah
Assefa, Samuel A.
Polley, Spencer D.
Manske, Magnus
MacInnis, Bronwyn
Rockett, Kirk A.
Maslen, Gareth L.
Sanders, Mandy
Quail, Michael A.
Chiodini, Peter L.
Kwiatkowski, Dominic P.
Clark, Taane G.
Sutherland, Colin J.
Journal Name PLoS One
Publication Date 2011
Volume Number 6
Issue Number 8
ISSN 1932-6203   (check CDU catalogue open catalogue search in new window)
Start Page e23204
Total Pages 11
Place of Publication United States
Publisher Public Library of Science
HERDC Category C1 - Journal Article (DEST)
Abstract Naturally acquired blood-stage infections of the malaria parasite Plasmodium falciparum typically harbour multiple haploid clones. The apparent number of clones observed in any single infection depends on the diversity of the polymorphic markers used for the analysis, and the relative abundance of rare clones, which frequently fail to be detected among PCR products derived from numerically dominant clones. However, minority clones are of clinical interest as they may harbour genes conferring drug resistance, leading to enhanced survival after treatment and the possibility of subsequent
therapeutic failure.

We deployed new generation sequencing to derive genome data for five non-propagated parasite isolates taken directly from 4 different patients treated for clinical malaria in a UK hospital. Analysis of depth of coverage and length of sequence intervals between paired reads identified both previously described and novel gene deletions and amplifications. Full-length sequence data was extracted for 6 loci considered to be under selection by antimalarial drugs, and both known and previously unknown amino acid substitutions were identified. Full mitochondrial genomes were extracted from the sequencing data for each isolate, and these are compared against a panel of polymorphic sites derived from published or unpublished but publicly available data.

Finally, genome-wide analysis of clone multiplicity was performed, and the number of infecting parasite clones estimated for each isolate. Each patient harboured at least 3 clones of P. falciparum by this analysis, consistent with results obtained with conventional PCR analysis of polymorphic merozoite antigen loci. We conclude that genome sequencing of peripheral blood P. falciparum taken directly from malaria patients provides high quality data useful for drug resistance studies, genomic structural analyses and population genetics, and also robustly represents clonal multiplicity.
DOI http://dx.doi.org/10.1371/journal.pone.0023204   (check subscription with CDU E-Gateway service for CDU Staff and Students  check subscription with CDU E-Gateway in new window)


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