title: Mitotic evolution of Plasmodium falciparum shows a stable core genome but recombination in antigen families.
abstract: 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.
authors: Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, California, USA.
authors: Selina E R
authors: SE
authors: Bopp
authors: Micah J
authors: MJ
authors: Manary
authors: A Taylor
authors: AT
authors: Bright
authors: Geoffrey L
authors: GL
authors: Johnston
authors: Neekesh V
authors: NV
authors: Dharia
authors: Fabio L
authors: FL
authors: Luna
authors: Susan
authors: S
authors: McCormack
authors: David
authors: D
authors: Plouffe
authors: Case W
authors: CW
authors: McNamara
authors: John R
authors: JR
authors: Walker
authors: David A
authors: DA
authors: Fidock
authors: Eros Lazzerini
authors: EL
authors: Denchi
authors: Elizabeth A
authors: EA
authors: Winzeler
mesh_terms: D000940:Antigenic Variation / Q000187:drug effects / Q000235:genetics; D000941:Antigens / Q000187:drug effects / Q000235:genetics; D053626:Atovaquone / Q000008:administration & dosage*; D045303:Cytochromes b / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000235:genetics; D019143:Evolution, Molecular; D018503:Genome, Protozoan / Q000187:drug effects; D059014:High-Throughput Nucleotide Sequencing; D006790:Host-Parasite Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D016778:Malaria, Falciparum / Q000235:genetics / Q000276:immunology; D008938:Mitosis / Q000235:genetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics / Q000276:immunology
chemical_list: D000941:Antigens; D053626:Atovaquone; D045303:Cytochromes b; D027425:ATP-Binding Cassette, Sub-Family C Proteins