Allele-specific expression in a family quartet with autism reveals mono-to-biallelic switch and novel transcriptional processes. Homo sapiens

Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder, and the exact causal mechanism is unknown. Dysregulated allele-specific expression (ASE) has been identified in persons with ASD; however, a comprehensive analysis of ASE has not been conducted in a family quartet with ASD. To fill this gap, we analyzed ASE using genomic DNA from parent and offspring and RNA from offspring’s postmortem prefrontal cortex (PFC); one of the two offspring had been diagnosed with ASD. DNA- and RNA-sequencing revealed distinct ASE patterns from both offspring PFC. However only the PFC of the offspring with ASD exhibited a mono-to-biallelic switch for LRP2BP and ZNF407. We also identified novel RNA-editing and monoallelically-expressed genes and miRNAs. Our results demonstrate the prevalence of ASE in human PFC and ASE abnormalities in the PFC of a person with ASD. Taken together, these findings may provide mechanistic insights into the pathogenesis of ASD. Overall design: We performed RNA-Seq on prefrontal cortex from subjects without and with autism and DNA-Seq on their and their parents' genomic DNA

孤独症谱系障碍（Autism spectrum disorder, ASD）是一类高患病率的神经发育障碍，其确切致病机制至今尚未明确。已有研究在孤独症患者群体中发现了失调的等位基因特异性表达（allele-specific expression, ASE），但针对携带孤独症患者的四人家庭开展的等位基因特异性表达全面分析仍属空白。为填补这一研究缺口，我们利用父母及子代的基因组DNA，以及子代死后前额叶皮层（prefrontal cortex, PFC）的RNA样本开展了等位基因特异性表达分析；本次研究的两名子代中，一名被诊断为孤独症。DNA测序与RNA测序结果显示，两名子代的前额叶皮层呈现出截然不同的等位基因特异性表达模式，但仅孤独症子代的前额叶皮层中，LRP2BP与ZNF407基因出现了单等位基因表达向双等位基因表达的转换。本研究还鉴定出了新型的RNA编辑基因、单等位表达基因以及微小RNA（miRNAs）。本研究结果证实了人类前额叶皮层中等位基因特异性表达的普遍性，同时揭示了孤独症患者前额叶皮层内的等位基因特异性表达异常。综上，这些研究结果可为孤独症的发病机制研究提供新的机制层面的见解。实验整体设计：我们对健康对照与孤独症患者的前额叶皮层开展了RNA测序，并对受试者及其父母的基因组DNA开展了DNA测序。