Sex- biasing influence of autism- associated Ube3a gene overdosage at connectomic, behavioral, and transcriptomic levels
July 12, 2024
Genomic mechanisms enhancing risk in males may contribute to sex bias in autism. 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 to 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.
Journal: Science Advances