Evaluating whole genome sequence data from the Genetic Absence Epilepsy Rat from Strasbourg and its related non-epileptic strain
Web of Science
AuthorCasillas-Espinosa, PM; Powell, KL; Zhu, M; Campbell, CR; Maia, JM; Ren, Z; Jones, NC; O'Brien, TJ; Petrovski, S
Source TitlePLoS One
PublisherPUBLIC LIBRARY SCIENCE
University of Melbourne Author/sO'Brien, Terence; Jones, Nigel; Casillas Espinosa, Pablo; Powell, Kim; Petrovski, Slave; Casillas Espinosa, Pablo Miguel
AffiliationMedicine and Radiology
Document TypeJournal Article
CitationsCasillas-Espinosa, P. M., Powell, K. L., Zhu, M., Campbell, C. R., Maia, J. M., Ren, Z., Jones, N. C., O'Brien, T. J. & Petrovski, S. (2017). Evaluating whole genome sequence data from the Genetic Absence Epilepsy Rat from Strasbourg and its related non-epileptic strain. PLOS ONE, 12 (7), https://doi.org/10.1371/journal.pone.0179924.
Access StatusOpen Access
OBJECTIVE: The Genetic Absence Epilepsy Rats from Strasbourg (GAERS) are an inbreed Wistar rat strain widely used as a model of genetic generalised epilepsy with absence seizures. As in humans, the genetic architecture that results in genetic generalized epilepsy in GAERS is poorly understood. Here we present the strain-specific variants found among the epileptic GAERS and their related Non-Epileptic Control (NEC) strain. The GAERS and NEC represent a powerful opportunity to identify neurobiological factors that are associated with the genetic generalised epilepsy phenotype. METHODS: We performed whole genome sequencing on adult epileptic GAERS and adult NEC rats, a strain derived from the same original Wistar colony. We also generated whole genome sequencing on four double-crossed (GAERS with NEC) F2 selected for high-seizing (n = 2) and non-seizing (n = 2) phenotypes. RESULTS: Specific to the GAERS genome, we identified 1.12 million single nucleotide variants, 296.5K short insertion-deletions, and 354 putative copy number variants that result in complete or partial loss/duplication of 41 genes. Of the GAERS-specific variants that met high quality criteria, 25 are annotated as stop codon gain/loss, 56 as putative essential splice sites, and 56 indels are predicted to result in a frameshift. Subsequent screening against the two F2 progeny sequenced for having the highest and two F2 progeny for having the lowest seizure burden identified only the selected Cacna1h GAERS-private protein-coding variant as exclusively co-segregating with the two high-seizing F2 rats. SIGNIFICANCE: This study highlights an approach for using whole genome sequencing to narrow down to a manageable candidate list of genetic variants in a complex genetic epilepsy animal model, and suggests utility of this sequencing design to investigate other spontaneously occurring animal models of human disease.
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