Iterative somatic epigenetic programming of behavior across multiple generations

摘要 遗传通常与孟德尔式的信息从父母传递到 通过等位基因产生后代，但经验数据清楚地表明，特征可以通过以下方式从祖先那里获得 不涉及DNA序列的机制。非基因传播的信息包括 父母经历，接触环境化学物质，滥用药物，父母突变和 改变父母环境的多态现象。观察到非遗传遗传已经有一段时间了 各种疾病，包括精神障碍。非遗传遗传并不限于第一种 后代的后代，但可以涉及孙辈，甚至更多的世代。而当 特征的多代传递通常被认为是配子的，我们之前证明了它 可以在怀孕期间通过躯体机制反复发生。我们指的是这种模式 行为特征的传递就像迭代的体细胞编程。我们最近发现， 焦虑和压力特征的多代非遗传传递是相关的，也可能是原因 母体自身免疫力代代相传。我们假设这位母亲 自身反应性抗体穿过胎盘，在后代中引起炎症，表现为 成年后的焦虑。这一假设将通过中断迭代编程的循环来检验 通过减轻母体自身免疫力和/或干扰母体自身免疫力的转移 母体通过各种免疫学方法产生针对胎儿的自身抗体。这项机械性的工作可能 有助于解释母亲的孩子自闭症和神经精神疾病发病率增加的原因 患有自身免疫性疾病。综上所述，我们的实验测试了一种可能有助于 与病理行为特征的反复躯体传递有关，特别是那些与 母体自身免疫。与遗传相反，性状的体细胞遗传并不是不可避免的，而且 因此，一旦更好地理解了潜在的机制，就可以防止这种情况的发生。

Abstract Inheritance is typically associated with the Mendelian transmission of information from parents to offspring by alleles, but empirical data clearly suggest that traits can be acquired from ancestors by mechanisms that do not involve DNA sequence. Information that is non-genetically transmitted includes parental experience, exposure to environmental chemicals, drugs of abuse, and parental mutations and polymorphisms that change the parental environment. Non-genetic inheritance has been observed for a wide range of diseases, including psychiatric disorders. Non-genetic inheritance is not limited to the first generation of the progeny, but can involve the grandchildren and even further generations. While multigenerational transmission of traits is typically believed to be gametic, we previously showed that it can occur iteratively through a somatic mechanism during gestation. We refer to this mode of transmission of behavioral traits as iterative somatic programming. We recently found that multigenerational non-genetic transmission of anxiety and stress traits is associated and perhaps caused by maternal autoimmunity perpetuating from one generation to the next. We hypothesize that maternal autoreactive antibodies cross the placenta and cause inflammation in the offspring, manifesting as anxiety in adulthood. This hypothesis will be tested by interrupting the cycle of iterative programming of offspring anxiety, by mitigating the maternal autoimmunity and/or interfering with the transfer of the maternal autoantibodies to the fetus by various immunological approaches. This mechanistic work may help explain the increased incidence of autism and neuropsychiatric conditions in children of mothers with autoimmune diseases. Taken together, our experiments test a novel mechanism that may contribute to the iterative somatic transmission of pathological behavioral traits, particularly those associated with maternal autoimmunity. In contrast to genetic, somatic inheritance of traits is not inevitable, and therefore could be prevented, once the underlying mechanism is better understood.