Department of Biomedical Sciences, University of South Carolina, Greenvile, South Carolina.
Department of Pediatrics, Prisma Health System, Greenville, South Carolina.
Autism Res. 2019 Jun;12(6):860-869. doi: 10.1002/aur.2112. Epub 2019 Apr 26.
Previous research on autism risk (ASD), developmental regulatory (DevReg), and central nervous system (CNS) genes suggests they tend to be large in size, enriched in nested repeats, and mutation intolerant. The relevance of these genomic features is intriguing yet poorly understood. In this study, we investigated the feature landscape of these gene groups to discover structural themes useful in interpreting their function, developmental patterns, and evolutionary history. ASD, DevReg, CNS, housekeeping, and whole genome control (WGC) groups were compiled using various resources. Multiple gene features of interest were extracted from NCBI/UCSC Bioinformatics. Residual variation intolerance scores, Exome Aggregation Consortium pLI scores, and copy number variation data from Decipher were used to estimate variation intolerance. Gene age and protein-protein interactions (PPI) were estimated using Ensembl and EBI Intact databases, respectively. Compared to WGC: ASD, DevReg, and CNS genes are longer, produce larger proteins, maintain greater numbers/density of conserved noncoding elements and transposable elements, produce more transcript variants, and are comparatively variation intolerant. After controlling for gene size, mutation tolerance, and clinical association, ASD genes still retain many of these same features. In addition, we also found that ASD genes that are extremely mutation intolerant have larger PPI networks. These data support many of the recent findings within the field of autism genetics but also expand our understanding of the evolution of these broad gene groups, their potential regulatory complexity, and the extent to which they interact with the cellular network. Autism Res 2019, 12: 860-869. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Autism risk genes are more ancient compared to other genes in the genome. As such, they exhibit physical features related to their age, including long gene and protein size and regulatory sequences that help to control gene expression. They share many of these same features with other genes that are expressed in the brain and/or are associated with prenatal development.
先前的自闭症风险（ASD）、发育调节（DevReg）和中枢神经系统（CNS）基因研究表明，它们往往体积较大，嵌套重复丰富，且对突变不宽容。这些基因组特征的相关性很有趣，但理解甚少。在这项研究中，我们研究了这些基因群的特征图谱，以发现有助于解释其功能、发育模式和进化历史的结构主题。ASD、DevReg、CNS、管家和全基因组对照（WGC）组使用各种资源进行编译。从 NCBI/UCSC 生物信息学中提取了多个感兴趣的基因特征。使用来自 Decipher 的残差变异不耐受评分、外显子组聚合联盟 pLI 评分和拷贝数变异数据来估计变异不耐受。使用 Ensembl 和 EBI Intact 数据库分别估计基因年龄和蛋白质-蛋白质相互作用（PPI）。与 WGC 相比：ASD、DevReg 和 CNS 基因更长，产生更大的蛋白质，维持更多/密度的保守非编码元件和转座元件，产生更多的转录变体，并且比较耐受变异。在控制基因大小、突变耐受性和临床关联后，ASD 基因仍然保留了许多相同的特征。此外，我们还发现，突变非常不耐受的 ASD 基因具有更大的 PPI 网络。这些数据支持自闭症遗传学领域的许多最新发现，但也扩展了我们对这些广泛基因群的进化、它们潜在的调控复杂性以及它们与细胞网络相互作用程度的理解。自闭症研究 2019, 12: 860-869。© 2019 自闭症国际研究协会，威利期刊，公司。
