Title
Next-Generation Sequencing of Plasmodium vivax Patient Samples Shows Evidence of Direct Evolution in Drug-Resistance Genes
Date Issued
08 January 2016
Access level
open access
Resource Type
journal article
Author(s)
Flannery E.
Wang T.
Akbari A.
Corey V.
Gunawan F.
Bright A.
Abraham M.
Edgel K.
Rosales L.
Bafna V.
Winzeler E.
U.S. Naval Medical Research Unit No. 6
U.S. Naval Medical Research Unit No. 6
U.S. Naval Medical Research Unit No. 6
U.S. Naval Medical Research Unit No. 6
University of California
Publisher(s)
American Chemical Society
Abstract
Understanding the mechanisms of drug resistance in Plasmodium vivax, the parasite that causes the most widespread form of human malaria, is complicated by the lack of a suitable long-term cell culture system for this parasite. In contrast to P. falciparum, which can be more readily manipulated in the laboratory, insights about parasite biology need to be inferred from human studies. Here we analyze the genomes of parasites within 10 human P. vivax infections from the Peruvian Amazon. Using next-generation sequencing we show that some P. vivax infections analyzed from the region are likely polyclonal. Despite their polyclonality we observe limited parasite genetic diversity by showing that three or fewer haplotypes comprise 94% of the examined genomes, suggesting the recent introduction of parasites into this geographic region. In contrast we find more than three haplotypes in putative drug-resistance genes, including the gene encoding dihydrofolate reductase-thymidylate synthase and the P. vivax multidrug resistance associated transporter, suggesting that resistance mutations have arisen independently. Additionally, several drug-resistance genes are located in genomic regions with evidence of increased copy number. Our data suggest that whole genome sequencing of malaria parasites from patients may provide more insight about the evolution of drug resistance than genetic linkage or association studies, especially in geographical regions with limited parasite genetic diversity.
Start page
367
End page
379
Volume
1
Issue
8
Language
English
OCDE Knowledge area
Medicina tropical Farmacología, Farmacia
Scopus EID
2-s2.0-84953252258
Source
ACS Infectious Diseases
Sponsor(s)
E.A.W. is supported by grants R01AI103058 and R01AI090141 from NIAID, grants from the Bill and Melinda Gates Foundation (OPP1040406), and the Medicines for Malaria Venture. E.L.F. is supported by an F32 NRSA fellowship (5F32AI102567). T.W. receives support from the UCSD Genetics Training Program through an institutional training grant from the National Institute of General Medical Sciences (T32 GM008666). The work in Peru was supported by U19AI089681 from NIAID (JMV). A.A. and V.B. were supported in part by a grant from the NSF (IIS-1318386). A.G.L. is sponsored by training grant 2D43 TW007393 awarded to NAMRU-6 by the Fogarty International Center of the U.S. National Institutes of Health. The views expressed in this article are those of the authors only and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government. Several authors of this manuscript are employees of the U.S. Government. This work was prepared as part of their duties. Title 17 U.S.C. § 105 provides that ''Copyright protection under this title is not available for any work of the United States Government.'' Title 17 U.S.C. § 101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person''s official duties.
Sources of information: Directorio de Producción Científica Scopus