Whole genome profiling of spontaneous and chemically induced mutations in Toxoplasma gondii

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• 作者：Andrew Farrell (8)
  Bradley I Coleman (8)
  Brian Benenati (8)
  Kevin M Brown (10) (9)
  Ira J Blader (11) (9)
  Gabor T Marth (8)
  Marc-Jan Gubbels (8)
  
  8. Department of Biology ; Boston College ; Higgins Hall 355 ; 140 Commonwealth Avenue ; Chestnut Hill ; MA ; 02467 ; USA
  10. Department of Molecular Microbiology ; Washington University School of Medicine ; MPRB 9230 ; 4940 Parkview Place ; St. Louis ; MO ; 63110 ; USA
  9. Department of Microbiology and Immunology ; University of Oklahoma Health Sciences Center ; 940 Stanton L. Young Blvd. ; BMSB 1053 ; Oklahoma City ; OK ; 73104 ; USA
  11. Department of Microbiology and Immunology ; State University of New York ; 138 Farber Hall ; 3435 Main Street ; Buffalo ; NY ; 14214 ; USA
  
• 关键词：Whole genome sequencing ; Chemical mutagenesis ; In vitro adaptation ; SNV calling ; Apicomplexa
• 刊名：BMC Genomics
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：15
• 期：1
• 全文大小：1,214 KB
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• 刊物主题：Life Sciences, general; Microarrays; Proteomics; Animal Genetics and Genomics; Microbial Genetics and Genomics; Plant Genetics & Genomics;
• 出版者：BioMed Central
• ISSN：1471-2164

文摘

Background Next generation sequencing is helping to overcome limitations in organisms less accessible to classical or reverse genetic methods by facilitating whole genome mutational analysis studies. One traditionally intractable group, the Apicomplexa, contains several important pathogenic protozoan parasites, including the Plasmodium species that cause malaria. Here we apply whole genome analysis methods to the relatively accessible model apicomplexan, Toxoplasma gondii, to optimize forward genetic methods for chemical mutagenesis using N-ethyl-N-nitrosourea (ENU) and ethylmethane sulfonate (EMS) at varying dosages. Results By comparing three different lab-strains we show that spontaneously generated mutations reflect genome composition, without nucleotide bias. However, the single nucleotide variations (SNVs) are not distributed randomly over the genome; most of these mutations reside either in non-coding sequence or are silent with respect to protein coding. This is in contrast to the random genomic distribution of mutations induced by chemical mutagenesis. Additionally, we report a genome wide transition vs transversion ratio (ti/tv) of 0.91 for spontaneous mutations in Toxoplasma, with a slightly higher rate of 1.20 and 1.06 for variants induced by ENU and EMS respectively. We also show that in the Toxoplasma system, surprisingly, both ENU and EMS have a proclivity for inducing mutations at A/T base pairs (78.6% and 69.6%, respectively). Conclusions The number of SNVs between related laboratory strains is relatively low and managed by purifying selection away from changes to amino acid sequence. From an experimental mutagenesis point of view, both ENU (24.7%) and EMS (29.1%) are more likely to generate variation within exons than would naturally accumulate over time in culture (19.1%), demonstrating the utility of these approaches for yielding proportionally greater changes to the amino acid sequence. These results will not only direct the methods of future chemical mutagenesis in Toxoplasma, but also aid in designing forward genetic approaches in less accessible pathogenic protozoa as well.