Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
NPJ Syst Biol Appl. 2022 Sep 6;8(1):31. doi: 10.1038/s41540-022-00243-8.
Autism spectrum disorders (ASD) are a set of complex neurodevelopmental diseases characterized with repetitive behavioral patterns and communication disabilities. Using a systems biology method called MAPSD (Markov Affinity-based Proteogenomic Signal Diffusion) for joint modeling of proteome dynamics and a wide array of omics datasets, we identified a list of candidate ASD risk genes. Leveraging the collected biological signals as well as a large-scale protein-protein interaction network adjusted based on single cell resolution proteome properties in four brain regions, we observed an agreement between the known and the newly identified candidate genes that are spatially enriched in neuronal cells within cerebral cortex at the protein level. Moreover, we created a detailed subcellular localization enrichment map of the known and the identified genes across 32 micro-domains and showed that neuronal cells and neuropils share the largest fraction of signal enrichment in cerebral cortex. Notably, we showed that the identified genes are among the transcriptional biomarkers of inhibitory and excitatory neurons in human frontal cortex. Intersecting the identified genes with a single cell RNA-seq data on ASD brains further evidenced that 20 candidate genes, including GRIK1, EMX2, STXBP6, and KCNJ3 are disrupted in distinct cell-types. Moreover, we showed that ASD risk genes are predominantly distributed in certain human interactome modules, and that the identified genes may act as the regulator for some of the known ASD loci. In summary, our study demonstrated how tissue-wide cell-specific proteogenomic modeling can reveal candidate genes for brain disorders that can be supported by convergent lines of evidence.
自闭症谱系障碍（ASD）是一组复杂的神经发育疾病，其特征是存在重复的行为模式和沟通障碍。我们使用一种称为 MAPSD（基于马尔可夫关联的蛋白质组学生物信号扩散）的系统生物学方法，对蛋白质组动力学和广泛的组学数据集进行联合建模，确定了一系列候选 ASD 风险基因。利用收集到的生物学信号以及基于四个脑区单细胞分辨率蛋白质组特性调整的大规模蛋白质-蛋白质相互作用网络，我们观察到已知和新鉴定的候选基因之间存在一致性，这些基因在蛋白质水平上在大脑皮层的神经元细胞中空间富集。此外，我们创建了一个详细的亚细胞定位图谱，显示了已知和鉴定基因在 32 个微区中的分布情况，并表明神经元细胞和神经突在大脑皮层中共享最大比例的信号富集。值得注意的是，我们表明鉴定出的基因是人类额叶皮质中抑制性和兴奋性神经元转录生物标志物之一。将鉴定出的基因与 ASD 大脑的单细胞 RNA-seq 数据进行交叉分析进一步表明，包括 GRIK1、EMX2、STXBP6 和 KCNJ3 在内的 20 个候选基因在不同的细胞类型中受到干扰。此外，我们表明 ASD 风险基因主要分布在某些人类相互作用模块中，并且鉴定出的基因可能作为一些已知 ASD 基因座的调节剂。总之，我们的研究表明，广泛的组织特异性蛋白质基因组建模如何揭示可以通过多种证据支持的大脑疾病候选基因。
