Pacific Northwest Diabetes Research Institute
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The Nadeau Lab studies the genetic, epigenetic and systems control of complex traits in mouse models of common human diseases. Most human disease results from interactions between genetic and environmental factors that are difficult to study in human populations. By contrast, genetically defined laboratory mice provide exceptional opportunities to study experimentally the ways in which genes and environment interact at multiple levels of biological functionality during development, through adulthood and across generations.
The lab’s work with chromosome substitution strains, which are genetically engineered to have single chromosome replacements on a defined inbred background, has revealed an unexpected picture of the genetic and phenotypic architecture of complex traits. In particular, the lab found that a very large number of genes with surprisingly large phenotypic effects and with strong interactions control biological variation. These insights emerge because substitution strains enable statistically powerful statements about the genetic and phenotypic properties of individual genotypes. This is an attribute that is not possible under genetically heterogeneous conditions, such as segregating crosses and human populations, where effects must be averaged across genetically distinct individuals.
However, despite these remarkable and unexpected properties, the Nadeau Lab has shown the gene discovery is nevertheless highly feasible, as demonstrated by the identification of two genes that confer resistance to diet-induced obesity and three genes that control susceptibility to testicular cancer. These substitution strains and related genetic resources facilitate discovery of disease genes, characterization of gene function, and analysis of epigenomic and systems properties.
Related studies focus on susceptibility to diet-induced non-alcoholic steato-hepatitis (NASH), hepatocellular carcinoma and intestinal neoplasia; the genetics and physiology of weight loss and repair of organ damage; and the genetic and developmental control of susceptibility to testicular cancer. Research currently underway focuses on the interplay between genetic, epigenetic and systems factors on diet-induced cancers and metabolic conditions as well as the developmental and genetic control of susceptibility to testicular cancer.
The Nadeau Lab also discovered the first evidence for transgenerational effects in mammals. Research showed that genetic variants in ancestral generations control phenotypic variation and disease risk across generations without subsequent inheritance of the initiating genetic variant. Although the impact of environmental factors on heritable epigenetic changes is established in plants, worms, and mammals, the fact that genetic variants can induce similar epigenetic changes was entirely unexpected. The lab showed that these heritable epigenetic changes involve a remarkable variety of phenotypic traits including cancers, metabolic disease and behaviors for multiple generations, with phenotypic effects that are comparable in magnitude to those that are inherited in a conventional Mendelian manner. The research also showed that these transgenerational effects result in part from aberrations in RNA biology. Together these studies suggest that inherited molecules, other than DNA, contribute to phenotypic variation and disease risk.
Ongoing work at the Nadeau Lab focuses on the molecular mechanisms that mediate heritable epigenetic changes, their modes of inheritance, the conditions under which these changes can be reversed, and the relevance of these effects in human populations.