Professor Dr Joe Nadeau PhD., Population Genetics, Institute for Systems Biology, Boston University, USA
Host: Prof Jonathan Flint
Abstract:
Organisms adapt developmental and physiological features to local and transient conditions in part by modulating transcription, translation and protein functions, usually without changing DNA sequences. Remarkably, these epigenetic changes sometimes endure through meiosis and gametogenesis, thereby affecting phenotypic variation across generations, long after the ancestral epigenetic features arose. These transgenerational effects violate the basic principle of Mendelian inheritance where phenotypes result from the direct action of environmental exposures and inherited genetics. Transgenerational effects therefore challenge our traditional understanding of inheritance and complicate conventional tests for associations between causal environmental and genetic factors with phenotypic and disease outcomes. Evidence for epigenetic inheritance is usually based on physical, chemical and biological exposures. However recent evidence also implicates genetic factors, both as inducers of epigenetic change as well as essential components of the underlying molecular mechanisms. Our recent work reveals important features of the genetic control of epigenetic inheritance: Both naturally-occurring genetic variants as well as engineered mutations can induce epigenetic inheritance. Some variants act in the maternal lineage, others in the paternal lineage, and still others in both. These changes are then propagated across generations in a lineage-specific manner. The phenotypic effects of epigenetic and conventional inheritance can be comparably strong. In both instances where tested, epigenetic control of phenotypic variation can be reversed after transmission for two consecutive generations through the alternative germline. The functions of several genes that control of susceptibility to testicular cancer implicate RNA editing and translation control in epigenetic inheritance. The exciting discovery of transgenerational epigenetic effects suggests that our understanding of the modes, mechanisms and molecules of inheritance may be incomplete in important ways. We now need to determine whether rules of segregation and transmission guide epigenetic inheritance and we need evidence for the molecular mechanisms linking epigenetic changes and phenotypic outcomes within and across generations.