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For reasons that remain unknown, the Plasmodium falciparum genome has an exceptionally high AT content compared to other Plasmodium species and eukaryotes in general - nearly 80% in coding regions and approaching 90% in non-coding regions. Here, we examine how this phenomenon relates to genome-wide patterns of de novo mutation. Mutation accumulation experiments were performed by sequential cloning of six P. falciparum isolates growing in human erythrocytes in vitro for 4 years, with 279 clones sampled for whole genome sequencing at different time points. Genome sequence analysis of these samples revealed a significant excess of G:C to A:T transitions compared to other types of nucleotide substitution, which would naturally cause AT content to equilibrate close to the level seen across the P. falciparum reference genome (80.6% AT). These data also uncover an extremely high rate of small indel mutation relative to other species, primarily associated with repetitive AT-rich sequences, in addition to larger-scale structural rearrangements focused in antigen-coding var genes. In conclusion, high AT content in P. falciparum is driven by a systematic mutational bias and ultimately leads to an unusual level of microstructural plasticity, raising the question of whether this contributes to adaptive evolution.

Original publication

DOI

10.1093/nar/gkw1259

Type

Journal article

Journal

Nucleic acids research

Publication Date

02/2017

Volume

45

Pages

1889 - 1901

Addresses

Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.

Keywords

Plasmodium falciparum, Reproducibility of Results, Phylogeny, Gene Expression Regulation, Recombination, Genetic, Base Composition, Mutation, Polymorphism, Single Nucleotide, Genome, Protozoan, INDEL Mutation, Mutation Rate