Master regulators of unexplained variation in disease risk

项目摘要 精准医学需要了解复杂性状的起源和分子控制， 疾病这一领域在很大程度上是由人类遗传学驱动的，它坚持1918年的教条，即表型是 完全由基因和环境决定。然而，来自同卵双胞胎和同基因动物的证据 模型表明，在不同的生理性状和疾病之间，高达50%的表型变异 可以用遗传学或环境来解释-有一些“更多”的东西对每个人来说都是独一无二的， 不能通过分析群体水平的平均效应来确定。这些发现还表明，即使我们 确实有“完整的”遗传和环境知识，疾病异质性的很大一部分将 仍然下落不明这个项目的运作假设是， 疾病异质性反映了生物系统固有的概率特性， 决定性的，真实的生物变异。有令人信服的证据表明进化的分子电路， 作为数量性状控制表型变异。因此，将变异性理解为一种数量性状， 对于理解表型多样性（一般）和个体疾病潜力的病因学至关重要 (in具体）。在这里，我们将开始最终回答精准医学的问题：什么是正常的， 对我来说有潜在的疾病吗那么，非遗传性、 人类的环境表型和疾病变异性？解决这些问题的第一步 识别概率过程导致疾病异质性的机制， 假定的变异调节因子和基因目录;表型、表观遗传和细胞变异图谱 绘制同基因模型系统（小鼠）中概率变化的景观;并且，为了证明， 变异控制的调节结构在小鼠和人类之间是保守的。如果这是真的， 无法解释的疾病异质性的重要部分是由于变异性本身的分子控制， 我们将发现一个全新的疾病病因学领域， 开发全新的预测，诊断和治疗干预措施，无论疾病是什么， 兴趣

PROJECT SUMMARY Precision medicine requires an understanding of the origins and molecular control over complex traits and disease. The field is largely driven by human genetics, which adheres to a 1918 dogma that phenotype is determined solely by genetics and the environment. Yet, evidence from monozygotic twins and isogenic animal models indicate that up to 50% of phenotypic variation across diverse physiological traits and diseases cannot be explained by genetics or environment – there is something `more' that is unique to each individual, and that cannot be determined by analyzing population-level mean effects. These findings also indicate that even if we did have `complete' genetic and environmental knowledge, a substantial portion of disease heterogeneity would remain unaccounted for. The operating hypothesis for this project is that a substantial fraction of unexplained disease heterogeneity reflects inherently probabilistic properties of the biological system that lead to fixed, deterministic, real biological variation. There is compelling evidence for an evolved molecular circuitry that controls phenotypic variability as a quantitative trait. Thus, understanding variability as a quantitative trait is essential to understanding the etiology of phenotypic diversity (in general) and an individual's disease potential (in particular). Here, we will begin to finally answer the precision medicine questions of: what is the normal or expected disease potential for me? And, what are the origins and regulatory controls of non-genetic, non- environmental phenotypic and disease variability in humans? The first steps towards addressing these questions and identifying mechanisms through which probabilistic processes lead to disease heterogeneity is to create a catalogue of putative variance regulators and genes; a phenotypic, epigenetic, and cellular variance atlas charting the landscape of probabilistic variation in an isogenic model system (mice); and, to demonstrate that the regulatory architecture of variance control is conserved between mouse and humans. If it is true that a significant portion of unexplained disease heterogeneity is due to the molecular control of variability itself, then we will have uncovered an entirely new area of disease etiology that can be harnessed by the community to develop fundamentally new predictive, diagnostic, and therapeutic interventions, irrespective of the disease of interest.