Studies of endogenous retrovirus activity in mice

小鼠基因组含有数千种内源性逆转录病毒（erv）。与人类的ERV活性停止不同，ERV插入在小鼠中引起许多突变，使小鼠成为研究ERV活性的良好模型。此外，由于小鼠被广泛用于人类发育和疾病的研究，因此了解ERV的控制机制和持续ERV活动的影响是很重要的。我们的长期目标是阐明小鼠ERV活动的后果和调控，我们有两个具体目标。第一个目标是确定在一种不寻常的小鼠品系C3H/HeJ中产生高ERV活性的机制。我们假设这种活性是由于菌株特异性的“主”ERV或由于宿主基因的遗传变异导致ERV表达增加。我们已经确定了六个ERV副本，我们将评估它们作为潜在的主副本，我们还将研究参与控制ERV活性的宿主因子。第二个目的是确定外显子ERV插入的影响。ERV插入基因编码外显子通常会受到负选择和消除。然而，由于小鼠品系的人工近亲繁殖，这种插入，如果不是致命的，可以留在一个品系内，因此可以解释品系之间的显着差异。最近发表的在18个菌株之间不同的ERV拷贝提供了丰富的数据，我们将利用这些数据来检验外显子ERV插入有助于菌株特异性遗传差异和性状的假设。最初的研究将集中在ERV在Scarf1和Plch2基因上的外显子插入，这些基因是特定于一个菌株的。这一目标将扩大，因为我们确定更多的菌株特异性外显子插入。目的1的结果应该为小鼠erv的调控以及宿主机制抑制erv和erv用来逃避这种抑制的途径之间的“军备竞赛”平衡提供新的理解。目的二的结果将提供深入了解如何ERV插入有助于菌株特异性变异和性状。我们的发现将在小鼠遗传学、逆转录病毒生物学、宿主防御和进化等领域具有广泛的意义。

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.