Early life environmental effects: molecular mechanisms and inter-individual variation

项目摘要 早期的生命环境可以对人类健康产生深远而持久的影响，但其机制基础 对这些影响的了解仍然很少，解释个体间差异的因素也是如此。这些差距存在于 知识严重限制了我们预测易感人群和制定有效干预措施的能力 战略。在分子水平上，早期生命对晚年健康的影响被认为是由稳定的 基因调控的变化。然而，许多基因调控元件对环境刺激有反应。 在整个生命过程中，分离早期生命状况的影响或了解它们的稳定性是一件具有挑战性的事情， 特别是在没有生命周期内环境变化或没有纵向数据的情况下。我的 研究计划旨在通过与两个最低生活水平的群体合作来克服这些挑战：1) 肯尼亚的图尔卡纳人，他们正在经历快速的生活方式变化，以至于早期生活和成年条件在很大程度上 与玻利维亚的齐马尼人脱钩，他们几十年来一直被纵向跟踪。在这两组人中，我 将生成与信息配对的全基因组基因调控数据集(DNA甲基化、基因表达 关于环境体验和健康，使我能够确定嵌入早期生命的机制 暴露在终生生理学中。我还将为每个个体生成全基因组的基因数据，按顺序 问基因变异是否预示着基因对早期生命挑战的敏感度和韧性 监管层面。最后，我将用基于实验室的方法来补充这项基于现场的观察工作 检测1)DNA甲基化和基因表达之间的因果关系，以及2)基因和 环境诱导的基因表达，两者都在高通量。在这样做的过程中，这个项目将揭开基因 调节早期生活对健康的影响的调节机制，以及这些影响的程度 基因变异会改变人与人的关系。通过“在实地”和“在实验室”工作，拟议的工作将 也有助于我们对自然人类的发展和环境过程的理解 作为因果机制。更广泛地说，拟议中的项目将把一个主要的全球现象联系起来--日益增长 城市化和市场一体化--基因调控过程和健康在两个未充分研究和 服务不足的人群(非洲人和美洲印第安人)。它还将生成新的方法和资源， 有助于我们理解人类复杂性状中基因x环境交互作用的一般模式。

Project Summary Early life environments can have profound and long-lasting effects on human health, yet the mechanistic basis of these effects remain poorly understood as do the factors that explain inter-individual variation. These gaps in knowledge severely limit our ability to both predict susceptible individuals and to develop effective intervention strategies. At the molecular level, early life effects on later life health are thought to be mediated by stable changes in gene regulation. However, many gene regulatory elements are responsive to environmental stimuli throughout life, making it challenging to isolate the effects of early life conditions or to understand their stability, especially when within-lifetime environmental variation is absent or longitudinal data are not available. My research program aims to overcome these challenges by working with two subsistence-level groups: 1) the Turkana of Kenya, who are experiencing rapid lifestyle change such that early life and adult conditions are largely decoupled and 2) the Tsimane of Bolivia, who have been followed longitudinally for decades. In both groups, I will generate genome-wide gene regulatory datasets (DNA methylation, gene expression) paired with information on environmental experiences and health, allowing me to identify the mechanisms that embed early life exposures into lifelong physiology. I will also generate genome-wide genotype data for each individual, in order to ask whether genetic variation predicts sensitivity versus resilience to early life challenges at the gene regulatory level. Finally, I will complement this field-based, observational work with lab-based methods capable of testing for causal connections between 1) DNA methylation and gene expression and 2) genotype and environmentally-induced gene expression, both in high-throughput. In doing so, this project will uncover the gene regulatory mechanisms that mediate early life effects on health, as well as the degree to which these relationships are modified by genetic variation. By working “in the field” and “in the lab”, the proposed work will inform our understanding of developmental and environmental processes in natural human populations as well as causal mechanisms. More broadly, the proposed projects will link a major global phenomenon—increasing urbanization and market-integration—with gene regulatory processes and health in two understudied and underserved populations (Africans and Amerindians). It will also generate new methods and resources that will inform our understanding of the general patterns of genotype x environment interactions in human complex traits.