Studies of endogenous retrovirus activity in mice

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The mouse genome contains many thousands of endogenous retroviruses (ERVs). Unlike in human where ERV activity has ceased, ERV insertions cause many mutations in mice, making the mouse an excellent model to study ERV activity. Moreover, because mouse is widely used for the study of human development and disease, it is important to gain an understanding of the mechanisms that control ERVs and of the effects of ongoing ERV activity. Our long-term goal is to elucidate the consequences and regulation of ERV activity in the mouse and we have two specific aims. The first aim is to identify the mechanism responsible for high ERV activity in an unusual mouse strain, C3H/HeJ. We hypothesize that such activity is due to a strain-specific "master" ERV or due to genetic variation in host gene(s) that allows increased ERV expression. We have identified six ERV copies that we will evaluate as potential master copies and we will also examine host factors involved in controlling ERV activity. The second aim is to determine the impact of exonic ERV insertions. ERV insertions into gene coding exons will normally be subject to negative selection and eliminated. However, due to artificial inbreeding of mouse strains, such insertions, if not lethal, can remain within a strain and therefore could account for significant differences between strains. The recent publication of ERV copies that vary between 18 strains provides a wealth of data that we will utilize to test the hypothesis that exonic ERV insertions contribute to strain-specific genetic differences and traits. Initial studies will focus on ERV exonic insertions in the Scarf1 and Plch2 genes that are specific to one strain. This aim will expand as we identify more strain-specific exonic insertions. Results of aim one should provide novel understanding of the regulation of mouse ERVs and of the "arms race" balance between host mechanisms to suppress ERVs and the pathways used by ERVs to escape such suppression. Results of aim two will provide insight into how ERV insertions contribute to strain-specific variation and traits. Our findings will be broadly significant for the fields of mouse genetics, retroviral biology, host defense and evolution.