Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, USA.
PLoS Genet. 2013;9(1):e1003221. doi: 10.1371/journal.pgen.1003221. Epub 2013 Jan 17.
Nucleotide changes in the AUTS2 locus, some of which affect only noncoding regions, are associated with autism and other neurological disorders, including attention deficit hyperactivity disorder, epilepsy, dyslexia, motor delay, language delay, visual impairment, microcephaly, and alcohol consumption. In addition, AUTS2 contains the most significantly accelerated genomic region differentiating humans from Neanderthals, which is primarily composed of noncoding variants. However, the function and regulation of this gene remain largely unknown. To characterize auts2 function, we knocked it down in zebrafish, leading to a smaller head size, neuronal reduction, and decreased mobility. To characterize AUTS2 regulatory elements, we tested sequences for enhancer activity in zebrafish and mice. We identified 23 functional zebrafish enhancers, 10 of which were active in the brain. Our mouse enhancer assays characterized three mouse brain enhancers that overlap an ASD-associated deletion and four mouse enhancers that reside in regions implicated in human evolution, two of which are active in the brain. Combined, our results show that AUTS2 is important for neurodevelopment and expose candidate enhancer sequences in which nucleotide variation could lead to neurological disease and human-specific traits.
AUTS2 基因座的核苷酸变化，其中一些仅影响非编码区域，与自闭症和其他神经发育障碍有关，包括注意缺陷多动障碍、癫痫、阅读障碍、运动延迟、语言延迟、视力障碍、小头畸形和饮酒。此外，AUTS2 包含区分人类和尼安德特人的基因组区域中加速最多的部分，主要由非编码变异组成。然而，这个基因的功能和调控仍然知之甚少。为了研究 auts2 的功能，我们在斑马鱼中敲低了它，导致头部尺寸变小、神经元减少和活动能力下降。为了研究 AUTS2 的调控元件，我们在斑马鱼和小鼠中测试了序列的增强子活性。我们鉴定了 23 个功能性的斑马鱼增强子，其中 10 个在大脑中具有活性。我们的小鼠增强子检测鉴定了三个与 ASD 相关缺失重叠的小鼠脑增强子和四个位于人类进化相关区域的小鼠增强子，其中两个在大脑中具有活性。综上所述，我们的研究结果表明，AUTS2 对神经发育很重要，并揭示了候选增强子序列，其中核苷酸变异可能导致神经发育疾病和人类特有的特征。
