Data Sheet 1_Transcripts derived from AmnSINE1 repetitive sequences are depleted in the cortex of autism spectrum disorder patients.zip

AimsAutism spectrum disorder (ASD) is a brain developmental disability with a not-fully clarified etiogenesis. Current ASD research largely focuses on coding regions of the genome, but up to date much less is known about the contribution of non-coding elements to ASD risk. The non-coding genome is largely made of DNA repetitive sequences (RS). Although RS were considered slightly more than “junk DNA”, today RS have a recognized role in almost every aspect of human biology, especially in developing human brain. Our aim was to test if RS transcription may play a role in ASD.
MethodsGlobal RS transcription was firstly investigated in postmortem dorsolateral prefrontal cortex of 13 ASD patients and 39 matched controls. Results were validated in independent datasets.
ResultsAmnSINE1 was the only RS significantly downregulated in ASD specimens. The role of AmnSINE1 in ASD has been investigated at multiple levels, showing that the 1,416 genes containing AmnSINE1 are associated with nervous system development and autism susceptibility. This has been confirmed in a different experimental setting, such as in organoid models of the human cerebral cortex, harboring different ASD causative mutations. AmnSINE1 related genes are transcriptionally co-regulated and are involved not only in brain formation but can specifically be involved in ASD development. Looking for a possible direct role of AmnSINE1 non-coding transcripts in ASD, we report that AmnSINE1 transcripts may alter the miRNA regulatory landscape for genes involved in neurogenesis.
ConclusionOur findings provide preliminary evidence supporting a role for AmnSINE1 in ASD development.

研究目的：自闭症谱系障碍（Autism Spectrum Disorder, ASD）是一种病因尚未完全阐明的脑部发育性残疾。当前自闭症研究多聚焦于基因组编码区域，但迄今为止，学界对非编码元件在自闭症风险中的贡献仍知之甚少。非编码基因组主要由DNA重复序列（DNA Repetitive Sequences, RS）构成。尽管重复序列曾被视作"垃圾DNA"，如今其在几乎所有人类生物学过程中均已被证实具有关键作用，尤其在人类大脑发育阶段。本研究旨在探究重复序列的转录过程是否在自闭症发病中发挥作用。
研究方法：本研究首先对13名自闭症患者与39名匹配对照者的死后背外侧前额叶皮层样本开展全局重复序列转录水平分析，研究结果在独立数据集内得到验证。
研究结果：AmnSINE1是唯一在自闭症样本中显著下调的DNA重复序列。我们从多个层面探究了AmnSINE1在自闭症中的作用，结果显示，携带AmnSINE1的1416个基因与神经系统发育及自闭症易感性密切相关。这一结论在不同实验模型中得到验证，例如在携带多种自闭症致病突变的人类大脑皮层类器官模型中。与AmnSINE1相关的基因存在转录共调控现象，它们不仅参与大脑发育过程，还可特异性地参与自闭症的发病进程。为探究AmnSINE1非编码转录本在自闭症中的潜在直接作用，本研究证实，AmnSINE1转录本可改变神经发生相关基因的微小RNA（miRNA）调控网络。
研究结论：本研究结果为AmnSINE1在自闭症发病机制中的作用提供了初步证据支持。