title: Extreme mutation bias and high AT content in Plasmodium falciparum.
abstract: 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.
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.|University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0SP, UK.
authors.forename: William L
authors.initials: WL
authors.lastname: Hamilton
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.|Medical Research Council Unit The Gambia, Atlantic Road, Fajara, P.O. Box 273, Banjul, The Gambia.|Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, London, WC1E 7HT, UK.
authors.forename: Antoine
authors.initials: A
authors.lastname: Claessens
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Otto
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.
authors.forename: Mihir
authors.initials: M
authors.lastname: Kekre
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Fairhurst
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.
authors.forename: Julian C
authors.initials: JC
authors.lastname: Rayner
authors.affiliation: Malaria Programme, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK.|Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK.
authors.forename: Dominic
authors.initials: D
authors.lastname: Kwiatkowski
mesh_terms: D001482:Base Composition; D005786:Gene Expression Regulation; D018503:Genome, Protozoan; D054643:INDEL Mutation; D009154:Mutation; D059645:Mutation Rate; D010802:Phylogeny; D010963:Plasmodium falciparum / Q000145:classification / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011995:Recombination, Genetic; D015203:Reproducibility of Results