Extreme mutation bias and high AT content in Plasmodium falciparum

Hamilton, W. L., Claessens, A., Otto, T. D. , Kekre, M., Fairhurst, R. M., Rayner, J. C. and Kwiatkowski, D. (2017) Extreme mutation bias and high AT content in Plasmodium falciparum. Nucleic Acids Research, 45(4), pp. 1889-1901. (doi: 10.1093/nar/gkw1259) (PMID:27994033) (PMCID:PMC5389722)

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.

• Item Type: Articles
• Additional Information: Wellcome Trust [098051]; Medical Research Council [G0600718]. Funding for open access charge: Wellcome Trust.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Otto, Professor Thomas
• Authors: Hamilton, W. L., Claessens, A., Otto, T. D., Kekre, M., Fairhurst, R. M., Rayner, J. C., and Kwiatkowski, D.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Nucleic Acids Research
• Publisher: Nature Publishing Group
• ISSN: 0305-1048
• ISSN (Online): 1362-4962
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Nucleic Acids Research 45(4):1889-1901
• Publisher Policy: Reproduced under a Creative Commons License