Studies of endogenous retrovirus activity in mice

小鼠基因组包含数千种内源性逆转录病毒(ERV)。与ERV活性已经停止的人类不同，ERV插入会在小鼠身上引起许多突变，使小鼠成为研究ERV活性的优秀模型。此外，由于小鼠被广泛用于研究人类发育和疾病，重要的是要了解控制ERV的机制和持续的ERV活动的影响。我们的长期目标是阐明ERV在小鼠体内活动的后果和调节，我们有两个具体的目标。第一个目标是确定在一种不寻常的小鼠品系C3H/HeJ中导致ERV高活性的机制。我们推测，这种活性是由于一种株系特异性的“主控”ERV，或由于宿主基因(S)的遗传变异，从而允许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，我们还将检查涉及控制ERV活性的宿主因素。第二个目标是确定外显子ERV插入的影响。ERV插入到基因编码外显子中通常会受到负选择和剔除。然而，由于老鼠品系的人工近亲繁殖，这种插入即使不是致命的，也可以保留在一个品系中，因此可以解释品系之间的显著差异。最近发表的18个菌株之间不同的ERV副本提供了丰富的数据，我们将利用这些数据来检验外显子插入有助于菌株特异性遗传差异和特征的假设。最初的研究将集中在ERV在Scarf1和Plch2基因上的外显子插入，这是一种毒株特有的。随着我们发现更多特定于菌株的外显子插入，这一目标将会扩大。AIM的结果应该提供对小鼠ERV的调节以及抑制ERV的宿主机制和ERV用来逃避这种抑制的途径之间的“军备竞赛”平衡的新理解。目标二的结果将提供对ERV插入如何有助于菌株特异性变异和特征的洞察。我们的发现将对小鼠遗传学、逆转录病毒生物学、宿主防御和进化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.