Background:We recently discovered autism/intellectual disability somatic mutations in postmortem brains, presenting higher frequency in Alzheimer’s disease subjects, compared with the controls. We further revealed high impact cytoskeletal gene mutations, coupled with potential cytoskeleton-targetedrepair mechanisms. Objective:The current study was aimed at further discerning if somatic mutations in brain diseases are presented only in the most affected tissue (the brain), or if blood samples phenocopy the brain, toward potential diagnostics. Methods:Variant calling analyses on an RNA-seq database including peripheral blood samples from 85 soldiers (58 controls and 27 with symptoms of post-traumatic stress disorder, PTSD) was performed. Results:High (e.g., protein truncating) as well as moderate impact (e.g., single amino acid change) germline and putative somatic mutations in thousands of genes were found. Further crossing the mutated genes with autism, intellectual disability, cytoskeleton, inflammation, and DNA repair databases, identified the highest number of cytoskeletal-mutated genes (187 high and 442 moderate impact). Most of the mutated genes were shared and only when crossed with the inflammation database, more putative high impact mutated genes specific to the PTSD-symptom cohorts versus the controls (14 versus 13) were revealed, highlighting tumor necrosis factor specifically in the PTSD-symptom cohorts. Conclusion:With microtubules and neuro-immune interactions playing essential roles in brain neuroprotection and Alzheimer-related neurodegeneration, the current mutation discoveries contribute to mechanistic understanding of PTSD and brain protection, as well as provide future diagnostics toward personalized military deployment strategies and drug design.

中文翻译：

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创伤后应激障碍症状士兵中推定的血液体细胞突变：细胞骨架和炎症蛋白的高影响

背景：我们最近在死后大脑中发现了自闭症/智力障碍的体细胞突变，与对照组相比，在阿尔茨海默病受试者中出现的频率更高。我们进一步揭示了高影响细胞骨架基因突变，以及潜在的细胞骨架靶向修复机制。目的：目前的研究旨在进一步辨别脑部疾病的体细胞突变是否仅出现在受影响最严重的组织（大脑）中，或者血液样本是否对大脑进行了表型复制，以进行潜在的诊断。方法：对包含来自 85 名士兵（58 名对照组和 27 名有创伤后应激障碍（PTSD）症状的士兵）外周血样本的 RNA-seq 数据库进行变体调用分析。结果：高（例如，蛋白质截断）以及中等影响（例如，单个氨基酸变化）在数千个基因中发现了种系和推定的体细胞突变。进一步将突变基因与自闭症、智力障碍、细胞骨架、炎症和 DNA 修复数据库进行交叉，确定了数量最多的细胞骨架突变基因（187 个高影响和 442 个中等影响）。大多数突变基因是共享的，并且只有在与炎症数据库交叉时，才会发现更多推定的、特定于 PTSD 症状队列的高影响突变基因与对照（14 对 13）相比，突出了 PTSD 症状中的肿瘤坏死因子队列。结论：微管和神经免疫相互作用在脑神经保护和阿尔茨海默相关神经变性中发挥重要作用，