Publication: Protein-based signatures of functional evolution in Plasmodium falciparum
3
Accepted Date
2011-09-14
Issued Date
2011-09-14
Copyright Date
2011
Resource Type
Language
eng
ISSN
1471-2148 (electronic)
Rights
Mahidol University
Rights Holder(s)
BioMed central
Bibliographic Citation
Gardner KB, Sinha I, Bustamante LY, Day NP, White NJ, Woodrow CJ. Protein-based signatures of functional evolution in Plasmodium falciparum. BMC Evol Biol. 2011 Sep 14;11:257.
Suggested Citation
Gardner, Kate B., Sinha, Ipsita, Bustamante, Leyla Y., Day, Nicholas P.J., White, Nicholas J., Woodrow, Charles J. Protein-based signatures of functional evolution in Plasmodium falciparum. Gardner KB, Sinha I, Bustamante LY, Day NP, White NJ, Woodrow CJ. Protein-based signatures of functional evolution in Plasmodium falciparum. BMC Evol Biol. 2011 Sep 14;11:257.. Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/679
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Title
Protein-based signatures of functional evolution in Plasmodium falciparum
Corresponding Author(s)
Abstract
BACKGROUND: It has been known for over a decade that Plasmodium falciparum
proteins are enriched in non-globular domains of unknown function. The potential
for these regions of protein sequence to undergo high levels of genetic drift
provides a fundamental challenge to attempts to identify the molecular basis of
adaptive change in malaria parasites.
RESULTS: Evolutionary comparisons were undertaken using a set of forty P.
falciparum metabolic enzyme genes, both within the hominid malaria clade (P.
reichenowi) and across the genus (P. chabaudi). All genes contained coding
elements highly conserved across the genus, but there were also a large number of
regions of weakly or non-aligning coding sequence. These displayed remarkable
levels of non-synonymous fixed differences within the hominid malaria clade
indicating near complete release from purifying selection (dN/dS ratio at
residues non-aligning across genus: 0.64, dN/dS ratio at residues identical
across genus: 0.03). Regions of low conservation also possessed high levels of
hydrophilicity, a marker of non-globularity. The propensity for such regions to
act as potent sources of non-synonymous genetic drift within extant P. falciparum
isolates was confirmed at chromosomal regions containing genes known to mediate
drug resistance in field isolates, where 150 of 153 amino acid variants were
located in poorly conserved regions. In contrast, all 22 amino acid variants
associated with drug resistance were restricted to highly conserved regions.
Additional mutations associated with laboratory-selected drug resistance, such as
those in PfATPase4 selected by spiroindolone, were similarly restricted while
mutations in another calcium ATPase (PfSERCA, a gene proposed to mediate
artemisinin resistance) that reach significant frequencies in field isolates were
located exclusively in poorly conserved regions consistent with genetic drift.
CONCLUSION: Coding sequences of malaria parasites contain prospectively definable
domains subject to neutral or nearly neutral evolution on a scale that appears
unrivalled in biology. This distinct evolutionary landscape has potential to
confound analytical methods developed for other genera. Against this tide of
genetic drift, polymorphisms mediating functional change stand out to such an
extent that evolutionary context provides a useful signal for identifying the
molecular basis of drug resistance in malaria parasites, a finding that is of
relevance to both genome-wide and candidate gene studies in this genus.