Roles of adaptive suppression of endogenous retroviruses in transgenerational non-genetic inheritance

Modern genetics explains evolution by accumulation of random mutations in DNA and survival of selected individuals. However, this scientific dogma is now challenged by an emerging notion that parental stresses can initiate heritable diseases without DNA mutations but involving persistent changes in mechanisms regulating activities of genes. It still remains controversial as to whether such epigenetic inheritance (EI) occurs in mammals, including humans. This question must be answered urgently because current medical sciences do not assume the risk that stresses in one generation could impact health of their grand-children or more distant offspring unless these chemicals create DNA mutations. The agouti viable yellow (Avy) strain of mouse is arguably one of few animal models of EI. The fur color of Avy mice varies randomly between yellow and brown, but offspring of a yellow mother tend to be biased to yellow. A virus-derived DNA sequence residing nearby the agouti gene, which determines fur color, is responsible for this apparent epigenetic inheritance. Activation of the virus also abnormally activates agouti, resulting in yellow fur. Unfortunately, because this color bias is so modest that its detection requires analysis of hundreds of offspring mice due to its mostly stochastic and untouchable nature, we still do not know exactly what is inherited to cause this bias in Avy mice. Taking advantage of the CRISPR/Cas9 genome editing technology, we will attempt to take direct and strong control of activation or suppression of the Avy virus in live animals. Our project will generate such genetically engineered versions of Avy mouse models as deliverables, providing unprecedented opportunities to identify heritable epigenetic marks in mammals. Thus, successful completion of our proposed study will change the mammalian EI research from the era of phenomenological controversy to the epoch of deeper mechanistic investigations.