Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.
Department of Immunology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.
Nat Commun. 2016 May 13;7:11492. doi: 10.1038/ncomms11492.
Parental behavioural traits can be transmitted by non-genetic mechanisms to the offspring. Although trait transmission via sperm has been extensively researched, epidemiological studies indicate the exclusive/prominent maternal transmission of many non-genetic traits. Since maternal conditions impact the offspring during gametogenesis and through fetal/early-postnatal life, the resultant phenotype is likely the aggregate of consecutive germline and somatic effects; a concept that has not been previously studied. Here, we dissected a complex maternally transmitted phenotype, reminiscent of comorbid generalized anxiety/depression, to elementary behaviours/domains and their transmission mechanisms in mice. We show that four anxiety/stress-reactive traits are transmitted via independent iterative-somatic and gametic epigenetic mechanisms across multiple generations. Somatic/gametic transmission alters DNA methylation at enhancers within synaptic genes whose functions can be linked to the behavioural traits. Traits have generation-dependent penetrance and sex specificity resulting in pleiotropy. A transmission-pathway-based concept can refine current inheritance models of psychiatric diseases and facilitate the development of better animal models and new therapeutic approaches.
父母的行为特征可以通过非遗传机制传递给后代。虽然通过精子传递特征已经得到了广泛的研究，但流行病学研究表明，许多非遗传特征是专门/主要通过母体传递的。由于母体状况会在配子发生过程中以及通过胎儿/早期产后生活影响后代，因此产生的表型很可能是连续的生殖系和体细胞效应的总和；这个概念以前没有被研究过。在这里，我们剖析了一种复杂的母体传递表型，这种表型类似于共患的广泛性焦虑/抑郁，以研究其在小鼠中的基本行为/领域及其传递机制。我们表明，四种焦虑/应激反应特征通过独立的迭代体和配子表观遗传机制在多个世代中传递。体/配子传递会改变突触基因增强子中的 DNA 甲基化，这些基因的功能可能与行为特征有关。特征具有世代依赖性的外显率和性别特异性，导致多效性。基于传递途径的概念可以完善当前的精神疾病遗传模型，并有助于开发更好的动物模型和新的治疗方法。
