Podium: The Genetic Mechanisms Driving Cerebellar Abiotrophy in Arabian Horses

Equine cerebellar abiotrophy (CA) is a hereditary neurodegenerative disease affecting the Purkinje neurons of the cerebellum, resulting in an ataxic phenotype.  It is inherited as an autosomal recessive trait and associated with a single nucleotide polymorphism (SNP) on equine chromosome 2 (CA SNP), which is located within a TOE1 exon and in proximity to MUTYH on the opposite strand. Unraveling which gene and associated pathway the CA SNP is affecting may elucidate the molecular mechanism of CA.  RNA-seq (100 bp PE strand-specific) was performed in cerebellar tissue of six CA-affected and five age-matched unaffected horses. Based on principle component analysis and dendogram plots, samples were clustered with four CA-affected and five CA-unaffected horses for further analyses.  Two pipelines for analysis of differentially expressed genes were used: Tophat2/Cufflinks/Cuffdiff2 and Kallisto/edgeR.  There were 195 significant differentially expressed genes in agreement between both analyses (FDR=0.05).  TOE1 (log(fold change)=0.51, q=0.618) and MUTYH (log(fold change)=0.03, q=0.992) were not among the differentially expressed genes. However, genes such as CALB1 (log(fold-change)=-4.6, q<0.001) and PCP2 (log(fold-change)=-3.26, q<0.001) that are specifically expressed in Purkinje neurons, were significantly under-expressed, as expected.  The cerebellar transcriptome includes expression of over 18,000 genes, of which several have extended UTRs and overlapping transcriptional regions.  This transcriptome annotation was essential in identifying other potential molecular mechanisms that may be affected by the CA SNP.