自闭症人类干细胞模型的发育趋同与分化，这一成果由加州大学Daniel H. Geschwind团队经过不懈努力而取得。该项研究成果发表在2026年1月29日出版的《自然》上。

为了确定ASD相关突变的共同和独特机制，课题组收集了大量患者的人类诱导多能干细胞（hiPS）细胞，包括70个经过严格质量控制的hiPS细胞系，代表8个ASD相关突变，特发性ASD，以及来自未受影响的对照个体的20个细胞系。

在这里，该研究组对这些hiPS细胞系进行了主题化，以产生人类皮质类器官，通过RNA测序在其不同的时间点进行分析，最长可达100体外分化后的天数。早期的时间点蕴藏着最大的突变特异性变化，但随着发育的进展，不同的突变聚集在共同的转录变化上。课题组发现了一个共享的RNA和蛋白质相互作用网络，该网络富含ASD风险基因，并预测会驱动观察到的下游基因表达变化。CRISPR-Cas9在诱导的人类神经祖细胞中筛选这些候选转录调控因子，验证了它们的下游趋同分子效应。这些数据阐明了与遗传定义的ASD形式相关的风险如何通过转录调控传播，从而影响趋同失调的途径，为ASD遗传风险对人类神经发育的趋同影响提供了新的见解。

研究人员表示，二十年来对自闭症谱系障碍（ASD）的遗传研究已经确定了100多个基因携带罕见的风险突变。尽管存在巨大的异质性，转录组学和表观遗传学分析已经确定了ASD死后大脑失调的趋同模式。

附：英文原文

Title: Developmental convergence and divergence in human stem cell models of autism

Author: Gordon, Aaron, Yoon, Se-Jin, Bicks, Lucy K., Martn, Jacqueline M., Pintacuda, Greta, Arteaga, Stephanie, Wamsley, Brie, Guo, Qiuyu, Elahi, Lubayna, Dolmetsch, Ricardo E., Bernstein, Jonathan A., OHara, Ruth, Hallmayer, Joachim F., Lage, Kasper, Pasca, Sergiu P., Geschwind, Daniel H.

Issue&Volume: 2026-01-29

Abstract: Two decades of genetic studies in autism spectrum disorder (ASD) have identified more than 100 genes harbouring rare risk mutations1,2,3,4,5,6,7,8,9,10,11,12,13. Despite this substantial heterogeneity, transcriptomic and epigenetic analyses have identified convergent patterns of dysregulation across the ASD postmortem brain14,15,16,17. To identify shared and distinct mechanisms of ASD-linked mutations, we assembled a large patient collection of human induced pluripotent stem (hiPS) cells, consisting of 70 hiPS cell lines after stringent quality control representing 8 ASD-associated mutations, idiopathic ASD, and 20 lines from non-affected control individuals. Here we used these hiPS cell lines to generate human cortical organoids, profiling by RNA sequencing at four distinct time points up to 100days after in vitro differentiation. Early time points harboured the largest mutation-specific changes, but different mutations converged on shared transcriptional changes as development progressed. We identified a shared RNA and protein interaction network, which was enriched in ASD risk genes and predicted to drive the observed downstream changes in gene expression. CRISPR–Cas9 screening of these candidate transcriptional regulators in induced human neural progenitors validated their downstream convergent molecular effects. These data illustrate how risk associated with genetically defined forms of ASD can propagate by means of transcriptional regulation to affect convergently dysregulated pathways, providing new insight into the convergent impact of ASD genetic risk on human neurodevelopment.

DOI: 10.1038/s41586-025-10047-5

Source: https://www.nature.com/articles/s41586-025-10047-5