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.

中文翻译：

---

自闭症相关 Ube3a 基因过量在连接组、行为和转录组水平的性别偏倚影响


增加男性风险的基因组机制可能导致自闭症的性别偏倚。泛素蛋白连接酶 E3A 基因 （ Ube3a ） 通过控制蛋白质更新和充当与类固醇激素受体的转录共激活因子来影响细胞稳态。通过染色体区域 15q11-13 的复制或三倍复制过量服用 Ube3a 会导致 1% 至 2% 的自闭症病例。在这里，我们检验了 Ube3a 剂量增加可能以性别偏倚的方式影响自闭症相关表型的假设。我们表明，具有额外 Ube3a 拷贝的小鼠对大脑连接组学和自闭症相关行为表现出性别偏倚效应。这些效应与自闭症相关基因的转录失调有关，以及在 15q 重复和自闭症患者中差异表达的基因。增加 Ube3a 剂量还会影响 X 染色体上基因的表达、受性类固醇激素影响的基因以及受转录因子性别差异调节的基因。这些结果表明，Ube3a 过量可以通过影响性别差异机制导致神经发育条件下的性别偏倚。