Low-complexity regions in Plasmodium falciparum: missing links in the evolution of an extreme genome

Abstract

Over the past decade, attempts to explain the unusual size and prevalence of low-complexity regions (LCRs) in the proteins of the human malaria parasite Plasmodium falciparum have used both neutral and adaptive models. This past research has offered conflicting explanations for LCR characteristics and their role in, and influence on, the evolution of genome structure. Here we show that P. falciparum LCRs (PfLCRs) are not a single phenomenon, but rather consist of at least three distinct types of sequence, and this heterogeneity is the source of the conflict in the literature. Using molecular and population genetics, we show that these families of PfLCRs are evolving by different mechanisms. One of these families, named here the HighGC family, is of particular interest because these LCRs act as recombination hotspots, both in genes under positive selection for high levels of diversity which can be created by recombination (antigens) and those likely to be evolving neutrally or under negative selection (metabolic enzymes). We discuss how the discovery of these distinct species of PfLCRs helps to resolve previous contradictory studies on LCRs in malaria and contributes to our understanding of the evolution of the of the parasite's unusual genome.

FIG. 1.

Loci and Plasmodium species used in the study. (A) Genes shown arranged by chromosomal position, both subtelomeric (areas of higher recombination) and central (regions of lower recombination) genes are represented in this study; (B) a phylogeny of the Plasmodium species used in comparisons for examining levels of divergence of the LCRs, showing the natural hosts and the evolutionary relationships of the parasites (dates from Escalante et al. [1995] and tree topology is from Perkins and Schall 2002).

FIG. 2.

Distribution of percent AT-content of all 28,607 LCRs in Plasmodium falciparum.

FIG. 3.

Cluster diagram showing the distinct groupings of PfLCR sequences by percent AT-content and heterozygosity. The larger shapes represent the mean values for each family.

FIG. 4.

Illustrative examples of each family of PfLCRs shown as amino acid alignments.

FIG. 5.

LCRs known to be recombinogenic in Plasmodium falciparum has low AT-content. AT-content distributions of known recombination breakpoints in LCRs, projected on the AT-content of all LCRs in the P. falciparum genome: Reticulocyte-binding protein 2 homologs A and 2 (RBP2) (Cortes 2005; Rayner et al. 2005), var genes (DePristo et al. 2006), MSP1 (Zilversmit MM, unpublished data), and MSP2 (Irion et al. 1997). See supplementary table 2 (Supplementary Material online) for PlasmoDB identification numbers and sequence data.