Transcriptional complexity and distinct expression patterns of auts2 paralogs in Danio rerio

Abstract

Several genes that have been implicated in autism spectrum disorders (ASDs) have multiple transcripts. Therefore, comprehensive transcript annotation is critical for determining the respective gene function. The autism susceptibility candidate 2 (AUTS2) gene is associated with various neurological disorders, including autism and brain malformation. AUTS2 is important for activation of transcription of neural specific genes, neuronal migration, and neurite outgrowth. Here, we present evidence for significant transcriptional complexity in the auts2 gene locus in the zebrafish genome, as well as in genomic loci of auts2 paralogous genes fbrsl1 and fbrs. Several genes that have been implicated in ASDs are large and have multiple transcripts. Neurons are especially enriched with longer transcripts compared to nonneural cell types. The human autism susceptibility candidate 2 (AUTS2) gene is ~1.2 Mb long and is implicated in a number of neurological disorders including autism, intellectual disability, addiction, and developmental delay. Recent studies show AUTS2 to be important for activation of transcription of neural specific genes, neuronal migration, and neurite outgrowth. However, much remains to be understood regarding the transcriptional complexity and the functional roles of AUTS2 in neurodevelopment. Zebrafish provide an excellent model system for studying both these questions. We undertook genomic identification and characterization of auts2 and its paralogous genes in zebrafish. There are four auts2 family genes in zebrafish: auts2a, auts2b, fbrsl1, and fbrs. The absence of complete annotation of their structures hampers functional studies. We present evidence for transcriptional complexity of these four genes mediated by alternative splicing and alternative promoter usage. Furthermore, the expression of the various paralogs is tightly regulated both spatially and developmentally. Our findings suggest that auts2 paralogs serve distinct functions in the development and functioning of target tissues.