Does organismal robustness explain the missing heritability in complex diseases?

描述（由申请人提供） 翻译后摘要：复杂的疾病，如糖尿病，癌症，心血管疾病和精神疾病往往聚集在家庭。因此，除了环境影响外，它们可能还涉及遗传因素。这些遗传因素的识别已被证明具有挑战性。虽然全基因组关联研究（GWAS）已经确定了许多与复杂疾病相关的遗传多态性，但其中大多数几乎没有疾病风险，并且不能解释家族中观察到的遗传性。这种差异被称为“缺失遗传性”，可以用不充分的基因分型、不精确的诊断和夸大的遗传性估计来解释。根据流行的假设，遗传易感性将转化为疾病与许多遗传修饰剂和环境因素相结合。我提出了一个替代假设：遗传易感性将转化为疾病的个人与降低有机体的鲁棒性。与复杂疾病相关的拷贝数变异的患者比对照组更可能携带额外的CNV。奇怪的是，许多额外的CNV是特定患者所特有的，这表明几乎有无限数量的遗传修饰剂。或者，增加的CNV负荷可能是不太稳健的表达，因此是致敏的遗传背景。在植物、苍蝇和鱼类中，生物体健壮性的下降增加了已知遗传变异的几率，并揭示了以前隐藏的遗传变异。已知遗传变异的增加和以前隐藏的变异的表达显着增加复杂性状的遗传力。如果将这些发现应用于复杂的人类疾病，则首先将评估所有个体的生物体稳健性程度，然后仅评估稳健性降低的个体中与疾病相关的遗传变异。这种方法取决于识别生物体稳健性的客观标记，优选地基于DNA或RNA，这可以在大的人群中容易地进行评估。我建议在一个遗传模式生物，植物A中确定生物体稳健性的客观分子标记。thaliana，通过将对照个体与通过主调节因子的靶向突变而变得不那么健壮的个体进行比较。我以前建立了A。thaliana作为一个非常适合的生物体鲁棒性模型，并确定了两个功能不同的主调节器，保持鲁棒性。我的假设进一步预测，在主调节器没有突变的情况下，生物体的鲁棒性在人类中是不同的。我将使用新发现的标记和传统的形态学措施来测试野生的，遗传多样的A。thaliana种群显示出生物体健壮性的分布。作为我的假设的原理证明，我将测试不太健壮的A。正如我的模型所预测的那样，拟南芥个体显示出更高的遗传变异和突变表达率。如果是这样的话，我将已经确定了生物体稳健性的分子标记，这些标记很容易适用于人类。通过考虑生物体的健壮性，复杂疾病将变得更具确定性，使我们能够更好地识别环境因素并定制治疗方法。 公共卫生相关性：在复杂的人类疾病中，遗传性缺失的原因是未能确定导致疾病的众多遗传修饰剂和环境暴露。根据最近关于复杂疾病患者突变负担增加的研究结果和我们的模式生物研究，我提出了另一种解释：遗传易感性将转化为生物体稳健性普遍下降的个体的疾病。采用遗传上易于处理的模式生物，我建议开发适用于大型人群的生物鲁棒性的分子标记，并在原理验证实验中测试其预测能力。

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.