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Variable Numbers of Tandem Repeats in Plasmodium falciparum Genes

Abstract

Genome variation studies in Plasmodium falciparum have focused on SNPs and, more recently, large-scale copy number polymorphisms and ectopic rearrangements. Here, we examine another source of variation: variable number tandem repeats (VNTRs). Interspersed low complexity features, including the well-studied P. falciparum microsatellite sequences, are commonly classified as VNTRs; however, this study is focused on longer coding VNTR polymorphisms, a small class of copy number variations. Selection against frameshift mutation is a main constraint on tandem repeats (TRs) in coding regions, while limited propagation of TRs longer than 975 nt total length is a minor restriction in coding regions. Comparative analysis of three P. falciparum genomes reveals that more than 9% of all P. falciparum ORFs harbor VNTRs, much more than has been reported for any other species. Moreover, genotyping of VNTR loci in a drug-selected line, progeny of a genetic cross, and 334 field isolates demonstrates broad variability in these sequences. Functional enrichment analysis of ORFs harboring VNTRs identifies stress and DNA damage responses along with chromatin modification activities, suggesting an influence on genome mutability and functional variation. Analysis of the repeat units and their flanking regions in both P. falciparum and Plasmodium reichenowi sequences implicates a replication slippage mechanism in the generation of TRs from an initially unrepeated sequence. VNTRs can contribute to rapid adaptation by localized sequence duplication. They also can confound SNP-typing microarrays or mapping short-sequence reads and therefore must be accounted for in such analyses.

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Acknowledgments

This study was supported by the National Institutes of Health (AI071121 and AI075145 to M.T.F), and an Arthur J. Schmitt Presidential Fellowship (to J.C.T.). We are grateful to F. Nosten, the Shoklo Malaria Research Unit, and T. Anderson for providing DNA samples, and the Broad Institute and Sanger Pathogen Sequencing Unit for making genome sequence data publicly available prior to publication. We acknowledge the Notre Dame Genomics Core Facility for excellent technical support.

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Correspondence to John C. Tan or Michael T. Ferdig.

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Tan, J.C., Tan, A., Checkley, L. et al. Variable Numbers of Tandem Repeats in Plasmodium falciparum Genes. J Mol Evol 71, 268–278 (2010). https://doi.org/10.1007/s00239-010-9381-8

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Keywords

  • Malaria genomics
  • Polymorphisms
  • Plasmodium falciparum
  • Copy number
  • Variable number tandem repeats
  • Intragenic tandem repeats