Department of Psychiatry, Stark Neurosciences Research Institute, Indiana University School of Medicine, 320 West 15th Street, Indianapolis, IN 46202, USA.
Department of Medical & Molecular Genetics, Indiana University School of Medicine, 320 West 15th Street, Indianapolis, IN 46202, USA.
Epigenomics. 2016 Mar;8(3):373-87. doi: 10.2217/epi.15.117. Epub 2016 Mar 7.
The origin of idiopathic diseases is still poorly understood. The latent early-life associated regulation (LEARn) model unites environmental exposures and gene expression while providing a mechanistic underpinning for later-occurring disorders. We propose that this process can occur across generations via transgenerational LEARn (tLEARn). In tLEARn, each person is a 'unit' accumulating preclinical or subclinical 'hits' as in the original LEARn model. These changes can then be epigenomically passed along to offspring. Transgenerational accumulation of 'hits' determines a sporadic disease state. Few significant transgenerational hits would accompany conception or gestation of most people, but these may suffice to 'prime' someone to respond to later-life hits. Hits need not produce symptoms or microphenotypes to have a transgenerational effect. Testing tLEARn requires longitudinal approaches. A recently proposed longitudinal epigenome/envirome-wide association study would unite genetic sequence, epigenomic markers, environmental exposures, patient personal history taken at multiple time points and family history.
特发性疾病的起源仍知之甚少。潜在的生命早期相关调节（LEARn）模型将环境暴露和基因表达结合起来，为后来发生的疾病提供了一种机制基础。我们提出，这个过程可以通过跨代 LEARn（tLEARn）在代际间发生。在 tLEARn 中，每个人都是一个“单位”，像原始的 LEARn 模型一样积累临床前或亚临床“命中”。这些变化可以通过表观遗传传递给后代。“命中”的跨代积累决定了散发性疾病状态。很少有重大的跨代“命中”会伴随大多数人的受孕或妊娠，但这些可能足以“启动”某人对以后生活中的“命中”做出反应。“命中”不需要产生症状或微表型就具有跨代效应。测试 tLEARn 需要采用纵向方法。最近提出的纵向全基因组/环境关联研究将结合遗传序列、表观遗传标记、环境暴露、在多个时间点采集的患者个人病史和家族病史。
