Does organismal robustness explain the missing heritability in complex diseases?

描述(由申请人提供) 摘要：糖尿病、癌症、心血管疾病和精神疾病等复杂疾病往往聚集在家族中。因此，除了环境影响外，它们可能还涉及遗传因素。事实证明，识别这些遗传因素具有挑战性。尽管全基因组关联研究已经发现了许多与复杂疾病相关的基因多态，但大多数这些多态几乎没有疾病风险，也不能解释观察到的家族遗传性。这种差异被称为“遗漏遗传力”，其原因是基因分型不充分、诊断不准确以及遗传力估算过高。在流行的假设下，遗传易感性会与众多的遗传修饰物和环境因素结合起来转化为疾病。我提出了另一种假设：在机体健壮性降低的个体中，遗传倾向会转化为疾病。与复杂疾病相关的拷贝数变异的患者比对照组更有可能携带额外的CNV。奇怪的是，许多额外的CNV是特定患者独有的，这表明几乎无限数量的遗传修饰物。或者，CNV负荷的增加可能是一种不那么健壮的、因此敏感的遗传背景的表现。在植物、苍蝇和鱼类中，生物稳健性的降低增加了已知遗传变异的外显性，并揭示了以前神秘的遗传变异。已知遗传变异的外显率和以前神秘变异的表达显著增加了复杂性状的遗传力。如果这些发现被应用于复杂的人类疾病，那么所有人都将首先被评估他们的机体健壮性程度，然后只在那些健壮性降低的人中评估与疾病相关的基因变异。这种方法取决于确定生物稳健性的客观标记，最好是基于DNA或RNA，这很容易在大量人类群体中进行评估。我建议通过比较对照个体和通过主调控子的定向突变而变得不那么健壮的个体，在遗传模式生物体--植物A.thaliana中识别生物健壮性的客观分子标记。我之前建立了A.thaliana作为一个非常适合生物稳健性的模型，并确定了两个在功能上不同的主调节因子来维持稳健性。我的假设进一步预测，在没有主调节器突变的情况下，不同人类的生物体健壮性是不同的。我将使用新识别的标记和传统的形态测量来测试野生、遗传多样性的拟南芥种群是否表现出生物体健壮性的分布。作为我的假设的原则性证明，然后我将测试不那么健壮的A.thaliana个体是否像我的模型预测的那样，表现出更高的遗传变异和突变表达能力。如果是这样的话，我将已经确定了生物健壮性的分子标记，这些标记很容易适用于人类。通过考虑生物体的稳健性，复杂的疾病将变得更具确定性，使我们能够更好地识别造成这些疾病的环境因素，并根据情况量身定制治疗方法。 与公共卫生的相关性：在复杂的人类疾病中，缺失的遗传性被解释为未能确定导致疾病的众多遗传修饰因素和环境暴露。在最近关于复杂疾病患者突变负担增加的发现和我们的模型生物体研究的推动下，我提出了另一种解释：在生物稳健性普遍降低的个人中，遗传易感性将转化为疾病。利用一种遗传上易驯化的模型生物，我建议开发适用于大量人类群体的生物稳健性分子标记，并在原理验证实验中测试它们的预测能力。

DESCRIPTION (Provided by the applicant) Abstract: Complex diseases such as diabetes, cancer, cardiovascular, and mental disease tend to cluster in families. Hence, they likely involve genetic factors in addition to environmental influences. The identification of these genetic factors has proven challenging. Although genome-wide association studies (GWAS) have identified many genetic polymorphisms that are associated with complex diseases, most of these confer little disease risk and do not explain the observed heritability in families. This discrepancy, called 'missing heritability', is explained with insufficient genotyping, imprecise diagnoses, and inflated heritability estimates. Under the prevalent hypothesis, genetic predispositions will translate into disease in combination with numerous genetic modifiers and environmental factors. I propose an alternative hypothesis: genetic predispositions will translate into disease in individuals with decreased organismal robustness. Patients with copy number variants associated with complex disease are more likely than controls to carry additional CNV. Curiously, many additional CNV are unique to particular patients, suggesting an almost infinite number of genetic modifiers. Alternatively, the increased CNV burden may be an expression of a less robust and therefore sensitized genetic background. In plants, flies, and fish, decreased organismal robustness increases the penetrance of known genetic variants and reveals formerly cryptic genetic variation. Increased penetrance of known genetic variants and expression of formerly cryptic variants significantly increases heritability of complex traits. If these findings were applied to complex human disease, all individuals would first be assessed for their degree of organismal robustness and then for genetic variants associated with disease only in those with decreased robustness. This approach hinges on identifying objective markers for organismal robustness, preferably based on DNA or RNA, which can be easily assessed in large human populations. I propose to identify objective molecular markers for organismal robustness in a genetic model organism, the plant A. thaliana, by comparing control individuals to individuals rendered less robust through targeted mutation of master regulators. I previously established A. thaliana as a well-suited model for organismal robustness and identified two functionally distinct master regulators that maintain robustness. My hypothesis further predicts that organismal robustness differs among humans in the absence of mutations in master regulators. I will use the newly identified markers and traditional morphological measures to test whether wild, genetically diverse A. thaliana populations show a distribution of organismal robustness. As proof of principle for my hypothesis, I will then test whether less robust A. thaliana individuals show higher expressivity of genetic variants and mutations as predicted by my model. If so, I will have identified molecular markers for organismal robustness that are readily applicable to humans. By accounting for organismal robustness, complex diseases will become more deterministic, allowing us to better identify the contributing environmental factors and to tailor treatments. Public Health Relevance: The missing heritability in complex human diseases has been explained with the failure to identify the numerous genetic modifiers and environmental exposures leading to disease. Prompted by recent findings on increased mutation burden in patients with complex disease and our model organism studies, I propose an alternative explanation: genetic predispositions will translate into disease in individuals with generally decreased organismal robustness. Employing a genetically tractable model organism, I propose to develop molecular markers for organismal robustness that are applicable in large human populations and to test their predictive power in proof-of-principle experiments.