The AUTS2 gene plays major roles during brain development and is associated with various neuropathologies including autism. Data in non-mammalian species are scarce, and the aim of our study was to provide a comprehensive analysis of auts2 evolution in teleost fish, which are widely used for in vivo functional analysis and biomedical purposes. Comparative genomics in 78 species showed that auts2a and auts2b originate from the teleost-specific whole genome duplication (TGD). auts2a, which is highly similar to human AUTS2, was almost systematically retained following TGD. In contrast, auts2b, which encodes for a shorter protein similar to a short human AUTS2 isoform, was lost more frequently and independently during evolution. RNA-seq analysis in 10 species revealed a highly conserved profile with predominant expression of both genes in the embryo, brain, and gonads. Based on protein length, conserved domains, and expression profiles, we speculate that the long human isoform functions were retained by auts2a, while the short isoform functions were retained by auts2a and/or auts2b, depending on the lineage/species. auts2a showed a burst in expression during medaka brain formation, where it was expressed in areas of the brain associated with neurodevelopmental disorders. Together, our data suggest a strong conservation of auts2 functions in vertebrates despite different evolutionary scenarios in teleosts.

AUTS2 gene has been associated with numerous human pathologies including autism. The respective importance of its maternal and paternal contribution remains however unknown. Here we show using a vertebrate model that the lack of maternal, but not paternal, gene contribution triggers reduced embryonic survival and long-term macroscopic and behavioral differences, including reduced head size and reduced environment recognition abilities and anxiety. Maternal auts2 modulates maternally-inherited factors that control, in turn, early embryonic gene expression through transcriptional and post-transcriptional regulations, and ultimately regulate numerous transcription factors and evolutionarily conserved signaling pathways during neurodevelopment. We observed a significant enrichment in genes associated with human neuropathologies among genes that are under maternal auts2control. We report that AUTS2 belongs to a group of 45 evolutionarily-conserved maternally-expressed genes associated with behavior and neurodevelopment in vertebrates and linked to a diversity of human diseases. These results shed new light on intergenerational determinism of neurodevelopment and behavior in vertebrates, including in the context of human pathologies associated with AUTS2.