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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.

SUBMITTER: Zilversmit MM

PROVIDER: S-EPMC2922621 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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

Zilversmit Martine M MM Volkman Sarah K SK DePristo Mark A MA Wirth Dyann F DF Awadalla Philip P Hartl Daniel L DL

Molecular biology and evolution 20100428 9

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 ...[more]

PMID: 20427419

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Project description:Malaria parasites elude eradication attempts both within the human host and across nations. At the individual level, parasites evade the host immune responses through antigenic variation. At the global level, parasites escape drug pressure through single nucleotide variants and gene copy amplification events conferring drug resistance. Despite their importance to global health, the rates at which these genomic alterations emerge have not been determined. We studied the complete genomes of different Plasmodium falciparum clones that had been propagated asexually over one year in the presence and absence of drug pressure. A combination of whole-genome microarray analysis and next-generation deep resequencing (totaling 14 terabases) revealed a stable core genome with only 38 novel single nucleotide variants appearing in seventeen evolved clones (avg. 5.4 per clone). In clones exposed to atovaquone, we found cytochrome b mutations as well as an amplification event encompassing the P. falciparum multidrug resistance associated protein (mrp1) on chromosome 1. We observed 18 large-scale (>1 kb on average) deletions of telomere-proximal regions encoding multigene families, involved in immune evasion (9.5×10(-6) structural variants per base pair per generation). Six of these deletions were associated with chromosomal crossovers generated during mitosis. We found only minor differences in rates between genetically distinct strains and between parasites cultured in the presence or absence of drug. Using these derived mutation rates for P. falciparum (1.0-9.7×10(-9) mutations per base pair per generation), we can now model the frequency at which drug or immune resistance alleles will emerge under a well-defined set of assumptions. Further, the detection of mitotic recombination events in var gene families illustrates how multigene families can arise and change over time in P. falciparum. These results will help improve our understanding of how P. falciparum evolves to evade control efforts within both the individual hosts and large populations.

Dataset Information

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

Publications

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

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