Genetic diversity and lack of artemisinin selection signature on the Plasmodium falciparum ATP6 in the Greater Mekong Subregion
The recent detection of clinical Artemisinin (ART) resistance manifested as delayed parasite clearance in the Cambodia-Thailand border area raises a serious concern. The mechanism of ART resistance is not clear; but the P. falciparum sarco/endoplasmic reticulum Ca(2+)-ATPase (PfSERCA or PfATP6)...
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Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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Format: | Article |
Language: | English |
Published: |
2014
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Subjects: | |
Online Access: | https://repository.li.mahidol.ac.th/handle/123456789/752 |
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Institution: | Mahidol University |
Language: | English |
Summary: | The recent detection of clinical Artemisinin (ART) resistance manifested as
delayed parasite clearance in the Cambodia-Thailand border area raises a serious
concern. The mechanism of ART resistance is not clear; but the P. falciparum
sarco/endoplasmic reticulum Ca(2+)-ATPase (PfSERCA or PfATP6) has been speculated
to be the target of ARTs and thus a potential marker for ART resistance. Here we
amplified and sequenced pfatp6 gene (~3.6 Kb) in 213 samples collected after 2005
from the Greater Mekong Subregion, where ART drugs have been used extensively in
the past. A total of 24 single nucleotide polymorphisms (SNPs), including 8 newly
found in this study and 13 nonsynonymous, were identified. However, these
mutations were either uncommon or also present in other geographical regions with
limited ART use. None of the mutations were suggestive of directional selection
by ARTs. We further analyzed pfatp6 from a worldwide collection of 862 P.
falciparum isolates in 19 populations from Asia, Africa, South America and
Oceania, which include samples from regions prior to and after deployments ART
drugs. A total of 71 SNPs were identified, resulting in 106 nucleotide
haplotypes. Similarly, many of the mutations were continent-specific and present
at frequencies below 5%. The most predominant and perhaps the ancestral haplotype
occurred in 441 samples and was present in 16 populations from Asia, Africa, and
Oceania. The 3D7 haplotype found in 54 samples was the second most common
haplotype and present in nine populations from all four continents. Assessment of
the selection strength on pfatp6 in the 19 parasite populations found that pfatp6
in most of these populations was under purifying selection with an average
d(N)/d(S) ratio of 0.333. Molecular evolution analyses did not detect significant
departures from neutrality in pfatp6 for most populations, challenging the
suitability of this gene as a marker for monitoring ART resistance. |
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