Uncovering 'Missing Heritability' in Any Experimentally Tractable Model Organism

Type of Award: Catalyst
Date Awarded: August 2014
Award End Date: July 2016
Amount Awarded: $ 200,000.00
PI(s): Erik Andersen, PhD, NU; Ilya Ruvinsky, PhD, UChicago;

Abstract: Completion of the human genome project provided a first glimpse at our genetic blueprint. However, the DNA sequence is only part of the story -- we must be able to interpret that genetic information. Previous studies showed that many traits, including disease susceptibility, are inherited in families, suggesting that identifying causal genes could be invaluable to diagnosis and treatment of these conditions. Over the past ten years, hundreds of genes that contribute to common disease have been identified. However, to our great surprise, they only predict a small fraction of the differences in disease susceptibility. How is it that these diseases have a strong genetic component yet we fail to identify most of the important genes? Plausible explanations range from genetic to statistical mechanisms. Importantly, none of these explanations can be feasibly tested in humans. Because these experiments are cost-prohibitive or impossible to do in humans, we propose to leverage the power of a model organism routinely used in biomedical research to rapidly test each of these hypotheses. Specifically, using Caenorhabditis elegans, we will: first create a large panel of reagents paired with high-throughput assays to achieve statistical power beyond what is possible in humans; this effort will define the bounds for genetic correlation studies in multicellular animals and second develop additional experimental measurement paradigms to determine how genetic contributions are altered by variable environments. Our project will empirically explore a vexing question, namely why genes identified so far explain little of the differences we see among individuals. It will thus contribute both to basic understanding of genetics and to the practical problem of identifying hereditary bases of susceptibility to common diseases in humans. This research effort will help to establish a long-term collaboration between two research groups that share common interests and possess complementary expertise.