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.
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