Evaluating whole genome sequence data from the Genetic Absence Epilepsy Rat from Strasbourg and its related non-epileptic strain

• DOI: 10.1371/journal.pone.0179924
• Publication Date: 2017-07-14T13:38:07Z
• Authors: Pablo M. Casillas...; Kim L. Powell; Mingfu Zhu; C. Ryan Campbell; Jessica M. Maia; Zhong Ren; Nigel C. Jones; Terence J. O’Brien; Slavé Petrovski
• Keywords: Male; 570; Genotype; Science; Polymorphism, Single Nucleotide; Calcium Channels, T-Type; 03 medical and health sciences; 0302 clinical medicine; 616; Genetics; Animals; Rats, Wistar; Genomes; Genome; Epilepsy; Q; R; Brain; High-Throughput Nucleotide Sequencing; Electroencephalography; DNA; Sequence Analysis, DNA; Genomics; Rats; Disease Models, Animal; Epilepsy, Absence; FOS: Biological sciences; Medicine; Female; Nucleotide sequence; Research Article

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.