{"title":"探索精神分裂症细胞特异性体细胞突变以及母体免疫激活对大脑体细胞突变的影响。","authors":"Jianbin Du, Yutaka Nakachi, Yui Murata, Emi Kiyota, Tadafumi Kato, Miki Bundo, Kazuya Iwamoto","doi":"10.1111/pcn.13640","DOIUrl":null,"url":null,"abstract":"<p><strong>Aim: </strong>Schizophrenia (SZ) is a severe psychiatric disorder caused by the interaction of genetic and environmental factors. Although somatic mutations that occur in the brain after fertilization may play an important role in the cause of SZ, their frequencies and patterns in the brains of patients and related animal models have not been well studied. This study aimed to find somatic mutations related to the pathophysiology of SZ.</p><p><strong>Methods: </strong>We performed whole-exome sequencing (WES) of neuronal and nonneuronal nuclei isolated from the postmortem prefrontal cortex of patients with SZ (n = 10) and controls (n = 10). After detecting somatic mutations, we explored the similarities and differences in shared common mutations between two cell types and cell type-specific mutations. We also performed WES of prefrontal cortex samples from an animal model of SZ based on maternal immune activation (MIA) and explored the possible impact of MIA on the patterns of somatic mutations.</p><p><strong>Results: </strong>We did not find quantitative differences in somatic mutations but found higher variant allele fractions of neuron-specific mutations in patients with SZ. In the mouse model, we found a larger variation in the number of somatic mutations in the offspring of MIA mice, with the occurrence of somatic mutations in neurodevelopment-related genes.</p><p><strong>Conclusion: </strong>Somatic mutations occurring at an earlier stage of brain cell differentiation toward neurons may be important for the cause of SZ. MIA may affect somatic mutation profiles in the brain.</p>","PeriodicalId":20938,"journal":{"name":"Psychiatry and Clinical Neurosciences","volume":null,"pages":null},"PeriodicalIF":5.0000,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Exploration of cell type-specific somatic mutations in schizophrenia and the impact of maternal immune activation on the somatic mutation profile in the brain.\",\"authors\":\"Jianbin Du, Yutaka Nakachi, Yui Murata, Emi Kiyota, Tadafumi Kato, Miki Bundo, Kazuya Iwamoto\",\"doi\":\"10.1111/pcn.13640\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Aim: </strong>Schizophrenia (SZ) is a severe psychiatric disorder caused by the interaction of genetic and environmental factors. Although somatic mutations that occur in the brain after fertilization may play an important role in the cause of SZ, their frequencies and patterns in the brains of patients and related animal models have not been well studied. This study aimed to find somatic mutations related to the pathophysiology of SZ.</p><p><strong>Methods: </strong>We performed whole-exome sequencing (WES) of neuronal and nonneuronal nuclei isolated from the postmortem prefrontal cortex of patients with SZ (n = 10) and controls (n = 10). After detecting somatic mutations, we explored the similarities and differences in shared common mutations between two cell types and cell type-specific mutations. We also performed WES of prefrontal cortex samples from an animal model of SZ based on maternal immune activation (MIA) and explored the possible impact of MIA on the patterns of somatic mutations.</p><p><strong>Results: </strong>We did not find quantitative differences in somatic mutations but found higher variant allele fractions of neuron-specific mutations in patients with SZ. In the mouse model, we found a larger variation in the number of somatic mutations in the offspring of MIA mice, with the occurrence of somatic mutations in neurodevelopment-related genes.</p><p><strong>Conclusion: </strong>Somatic mutations occurring at an earlier stage of brain cell differentiation toward neurons may be important for the cause of SZ. 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引用次数: 0
摘要
目的:精神分裂症(SZ)是一种由遗传和环境因素相互作用引起的严重精神障碍。虽然受精后在大脑中发生的体细胞突变可能在 SZ 的病因中扮演重要角色,但其在患者和相关动物模型大脑中的频率和模式尚未得到很好的研究。本研究旨在寻找与SZ病理生理学相关的体细胞突变:我们对从SZ患者(10人)和对照组(10人)死后前额叶皮层中分离出来的神经元和非神经元核团进行了全外显子组测序(WES)。在检测到体细胞突变后,我们探讨了两种细胞类型之间共同突变和细胞类型特异性突变的异同。我们还对基于母体免疫激活(MIA)的SZ动物模型的前额叶皮层样本进行了WES检测,并探讨了MIA对体细胞突变模式可能产生的影响:结果:我们没有发现体细胞突变的数量差异,但发现 SZ 患者神经元特异性突变的变异等位基因比例较高。在小鼠模型中,我们发现 MIA 小鼠后代的体细胞突变数量差异较大,神经发育相关基因的体细胞突变也较多:结论:在脑细胞向神经元分化的早期阶段发生的体细胞突变可能是导致SZ的重要原因。MIA可能会影响大脑中的体细胞突变情况。
Exploration of cell type-specific somatic mutations in schizophrenia and the impact of maternal immune activation on the somatic mutation profile in the brain.
Aim: Schizophrenia (SZ) is a severe psychiatric disorder caused by the interaction of genetic and environmental factors. Although somatic mutations that occur in the brain after fertilization may play an important role in the cause of SZ, their frequencies and patterns in the brains of patients and related animal models have not been well studied. This study aimed to find somatic mutations related to the pathophysiology of SZ.
Methods: We performed whole-exome sequencing (WES) of neuronal and nonneuronal nuclei isolated from the postmortem prefrontal cortex of patients with SZ (n = 10) and controls (n = 10). After detecting somatic mutations, we explored the similarities and differences in shared common mutations between two cell types and cell type-specific mutations. We also performed WES of prefrontal cortex samples from an animal model of SZ based on maternal immune activation (MIA) and explored the possible impact of MIA on the patterns of somatic mutations.
Results: We did not find quantitative differences in somatic mutations but found higher variant allele fractions of neuron-specific mutations in patients with SZ. In the mouse model, we found a larger variation in the number of somatic mutations in the offspring of MIA mice, with the occurrence of somatic mutations in neurodevelopment-related genes.
Conclusion: Somatic mutations occurring at an earlier stage of brain cell differentiation toward neurons may be important for the cause of SZ. MIA may affect somatic mutation profiles in the brain.
期刊介绍:
PCN (Psychiatry and Clinical Neurosciences)
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Published 12 online issues a year by JSPN
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