Extreme mutation bias and high AT content in Plasmodium falciparum

William L Hamilton , Antoine Claessens (1) , Thomas Otto (2) , Mihir Kekre , Rick M Fairhurst (3) , Julian C Rayner , Dominic Kwiatkowski (4)

1 The Wellcome Trust Sanger Institute [Cambridge]
2 TU - Technische Universität Ilmenau
3 Laboratory of Malaria and Vector Research
4 The Wellcome Trust Centre for Human Genetics [Oxford]

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. fal-ciparum 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 mu-tational bias and ultimately leads to an unusual level of microstructural plasticity, raising the question of whether this contributes to adaptive evolution.

Domaines: Parasitologie; Génétique des populations [q-bio.PE]; Génomique, Transcriptomique et Protéomique [q-bio.GN]

William L Hamilton, Antoine Claessens, Thomas Otto, Mihir Kekre, Rick M Fairhurst, et al.. Extreme mutation bias and high AT content in Plasmodium falciparum. Nucleic Acids Research, 2016, pp.gkw1259. ⟨10.1093/nar/gkw1259⟩. ⟨hal-01989279⟩