The Role of Natural Variation and Proteostasis in Complex Disease Traits

Type of Award: Spark
Date Awarded: March 2009
Award End Date: February 2011
Amount Awarded: $ 400,000.00
PI(s): Martin Kreitman, PhD, UChicago; Ilya Ruvinsky, PhD, UChicago; Richard Morimoto, PhD, NU;

Abstract: Our project "The Role of Natural Variation and Proteostasis in Complex Disease Traits", will attempt to create a new paradigm for studying human diseases with multifactorial genetic and environmental causes. Modern molecular genetics has triumphed over the past decade in the discovery of major mutations causing important human genetic diseases. But many diseases, such as adult-onset diabetes and autism, are not caused by mutations in single genes, but instead are characterized by a complex, and yet unknown, interaction between genetic variations in large number of genes and subtle environmental factors. For these diseases, molecular genetics has been much less successful in deciphering their genetic underpinnings. Our project, a collaboration between two evolutionary geneticists, Dr. Martin Kreitman and Ilya Ruvinsky (Department of Ecology and Evolution, U. Chicago), and a molecular geneticist, Dr. Richard Morimoto (Biochemistry, Molecular and Cell Biology, Northwestern U), proposes a novel way forward by investigating natural variation for susceptibility and severity of complex human disease, recreated in two model organisms, the fruitfly Drosophila melanogaster and the worm Caenorhabditis elegans. The two human diseases we will investigate -- neurodegeneration and neonatal diabetes -- share a common attribute in that they both result from the inability of targeted cells to respond to physiological stresses imposed by the expression of unstable mutant proteins. The inability of cells to respond to these stresses results in programmed cell death, the direct cause of disease. According to our working hypothesis, a complex diffuse web of interacting naturally occurring polymorphisms in fly, worm and human sets an individual's ability to respond to genetic or environmental challenges, determining susceptibility to and severity of disease. We will, for the first time, investigate naturally occurring variation affecting disease models in powerful model genetic systems, which we believe has the potential to revolutionize the use of disease these models. The goal of our experiments will be to identify cellular and genetic mechanisms in the worm and fly that influence the severity of these model diseases, taking advantage of the many power genetic and molecular tools available in these model organisms. We believe that commonalities in the worm and fly will also prove to be shared with the human form of the diseases, and that discoveries in these model organisms will therefore be relevant to developing novel therapies to disease. Our findings about effects of genetic variation on the ability of a cell to balance protein synthesis, folding, transport, and degradation (proteostasis), may have broader relevance to other sporadic diseases, in addition to diabetes and neurodegenerative disease. More generally, by integrating the study of natural genetic variation in model organisms with human genetic diseases recreated in these organisms, our research holds the promise of introducing powerful new strategy for deciphering the genetic basis of complex human disease.