Sex-biasing influence of autism-associated Ube3a gene overdosage at connectomic, behavioral and transcriptomic levels

Autism affects males more than females. Genomic mechanisms enhancing risk in males may 
contribute to this sex-bias. The Ubiquitin protein ligase E3A gene (Ube3a) affects cellular 
homeostasis via control of protein turnover, and by acting as transcriptional coactivator with 
steroid hormone receptors. Overdosage of Ube3a via duplication or triplication of chromosomal 
region 15q11-13 causes 1-2% of autistic cases. Here, we test the hypothesis that increased dosage 
of Ube3a may influence autism-relevant phenotypes in a sex-biased manner. We show that mice 
with extra copies of Ube3a exhibit sex-biasing effects on brain connectomics and autism-relevant 
behaviors. These effects are associated with transcriptional dysregulation of autism-associated 
genes, as well as genes differentially-expressed in 15q duplication and in autistic people. Increased 
Ube3a dosage also affects expression of genes on the X chromosome, genes influenced by sex 
steroid hormone and genes sex-differentially regulated by transcription factors. These results 
suggest that Ube3a overdosage can contribute to sex-bias in neurodevelopmental conditions via 
influence on sex-differential mechanisms.