Variable SNP density in aspartyl-protease genes of the malaria parasite Plasmodium falciparum.
An analysis of the diversity of the aspartyl proteases of Plasmodium falciparum, known as plasmepsins (PMs), was completed in view of their possible role as drug targets. DNA sequence polymorphisms were identified in nine pm genes including their non-coding (introns and 5' flanking) sequences. All genes contained at least one single nucleotide polymorphism (SNP). Extensive microsatellite diversity was observed predominantly in non-coding sequences. All but one non-synonymous polymorphism (a conservative substitution) were mapped to the surface of the predicted protein, contradicting a possible role in enzymatic activity. The distribution of SNPs was found to be non-random among pm genes, with pm6 and pm10 having significantly higher SNP densities, suggesting they were under selection. For pm6 the majority of the SNPs were in introns and some of these may contribute to splice site variation. SNPs were found at a high density in both the coding and non-coding sequences of pm10. Recombination was important in generating additional diversity at this locus. Although direct selection for pm10 mutations could not be ruled out, the presence of balancing selection and a high density of SNPs in non-coding sequence led us to propose that another gene under selection may be influencing the diversity in the region. By sequencing short DNA tags in a 200 kb region flanking pm10 we show that a cluster of antigen genes, known to be under diversifying selection, may contribute to the observed diversity. We discuss the importance of diversity and local selection effects when choosing drug targets for intervention strategies.
Barry
Alyssa E
AE
Peter Medawar Building for Pathogen Research and Zoology Department, University of Oxford, South Parks Road, Oxford, OX1 3SY, UK. alyssa.barry@med.nyu.edu
Leliwa-Sytek
Aleksandra
A
Man
Kitty
K
Kasper
Jacob M
JM
Hartl
Daniel L
DL
Day
Karen P
KP
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D001483:Base Sequence; D002874:Chromosome Mapping; D002875:Chromosomes; D016054:DNA, Protozoan / Q000235:genetics; D019143:Evolution, Molecular; D005787:Gene Frequency; D017125:Genes, Protozoan; D014644:Genetic Variation; D007438:Introns; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D009154:Mutation; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics* / Q000302:isolation & purification; D020641:Polymorphism, Single Nucleotide; D011995:Recombination, Genetic; D012641:Selection, Genetic; D017422:Sequence Analysis, DNA
D016054:DNA, Protozoan; D016282:Aspartic Acid Endopeptidases