Genomic heterogeneity in the density of noncoding single-nucleotide and microsatellite polymorphisms in Plasmodium falciparum

Abstract

The density and distribution of single-nucleotide polymorphisms (SNPs) across the genome has important implications for linkage disequilibrium mapping and association studies, and the level of simple-sequence microsatellite polymorphisms has important implications for the use of oligonucleotide hybridization methods to genotype SNPs. To assess the density of these types of polymorphisms in P. falciparum, we sampled introns and noncoding DNA upstream and downstream of coding regions among a variety of geographically diverse parasites. Across 36,229 base pairs of noncoding sequence representing 41 genetic loci, a total of 307 polymorphisms including 248 polymorphic microsatellites and 39 SNPs were identified. We found a significant excess of microsatellite polymorphisms having a repeat unit length of one or two, compared to those with longer repeat lengths, as well as a nonrandom distribution of SNP polymorphisms. Almost half of the SNPs localized to only three of the 41 genetic loci sampled. Furthermore, we find significant differences in the frequency of polymorphisms across the two chromosomes (2 and 3) examined most extensively, with an excess of SNPs and a surplus of polymorphic microsatellites on chromosome 3 as compared to chromosome 2 (P = 0.0001). Furthermore, at some individual genetic loci we also find a nonrandom distribution of polymorphisms between coding and flanking noncoding sequences, where completely monomorphic regions may flank highly polymorphic genes. These data, combined with our previous findings of nonrandom distribution of SNPs across chromosome 2, suggest that the Plasmodium falciparum genome may be a mosaic with regard to genetic diversity, containing chromosomal regions that are highly polymorphic interspersed with regions that are much less polymorphic.

Comparative genomic analysis of simple sequence repeats in three Plasmodium species

“…Further, approximate equal abundance of mono-and di-repeats with length ≥10 NT and ≥15 NT reflects high length variability in these repeat types. The results corroborate earlier studies where long repeat types were found to be more stable than the short ones (Volkman et al 2007). The present study also notifies that mono-(in P. vivax and P. knowlesi) and di-repeats (in P. falciparum) can serve as perfect molecular marker in population genetic studies as these repeat types show high length variability in individual genomes.…”

Variable Numbers of Tandem Repeats in Plasmodium falciparum Genes

“…Furthermore, these TRs were inherited in a Mendelian fashion in progeny of a genetic cross indicating short-term stability through meiosis and mitosis (data not shown). More extensive studies will be required to determine the stability of VNTRs and the rate at which these mutations occur, however, other studies indicate that indels/TRs provide at least as much polymorphism as SNPs in P. falciparum (Volkman et al 2007a, b). …”

Advances in understanding the genetic basis of antimalarial drug resistance

“…This presumably reflects the influence of diversifying selection exerted on genes by factors such as host immunity and drug selection. [4][5][6][7][8]. High rates of recombination, such as that observed among African P. falciparum strains [7], will tend to obscure the linkage between ancestral traits.…”