Extreme mutation bias and high AT content in Plasmodium falciparum

• Published in: Nucleic acids research 2017-02, Vol.45 (4), p.1889-1901
• Main Authors: Hamilton, William L, Claessens, Antoine, Otto, Thomas D, Kekre, Mihir, Fairhurst, Rick M, Rayner, Julian C, Kwiatkowski, Dominic
• Format: Article
• Language: English
• Subjects: Base Composition; Biochemistry, Molecular Biology; Gene Expression Regulation; Genetics; Genome, Protozoan; Genomics; INDEL Mutation; Life Sciences; Microbiology and Parasitology; Mutation; Mutation Rate; Parasitology; Phylogeny; Plasmodium falciparum - classification; Plasmodium falciparum - genetics; Polymorphism, Single Nucleotide; Populations and Evolution; Recombination, Genetic; Reproducibility of Results
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkw1259

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.