Causes and human health consequences of the evolution of retroelements and host restriction factors

 描述(申请人提供)：灵长类动物和它们的内源性逆转录元件已经共同进化了很长时间，以至于几乎一半的人类基因组来自逆转录元件序列。然而，逆转录元件的复制有可能通过进入必要基因或激活免疫系统来驱动自身免疫，从而造成实质性损害。为了对抗这些对它们基因组的有害影响，宿主进化出了一系列限制因子来阻止逆转录元件的复制。尽管它们对东道主健身很重要，但我有 研究发现，在灵长类动物的进化过程中，许多这些逆转录元件限制因子都进化得很快，这表明它们已经被反复选择用于功能创新。我假设灵长类和它们的内源性逆转录元件正在进行一场“进化军备竞赛”，即一个循环，即逃避和限制-逆转录元件适应以逃避宿主限制，然后宿主适应以限制新逃避的逆转录元件。此外，我的初步发现表明，除了内源性逆转录因子外，一些限制因子，如APOBEC3A，也可能被增选来限制传染性病毒。在目标1中，我建议描述APOBEC3A和APOBEC3B限制因子快速进化的原因和后果，包括这些因素如何进化来追逐L1逆转录元件，以及APOBEC3A限制传染性病毒的共同选择如何影响其限制内源性逆转录元件的能力。在目标2中，我建议测试L1TD1(一种快速进化的干细胞特异性基因，从L1的一部分驯化而来)作为逆转录因子限制因子的假设。在目标3中，我建议使用进化分析，以及设计一个体外进化系统来测试变异是否确实可以增加逆转录元件的复制并对宿主施加选择性压力。虽然我过去的训练使我能够产生这些有趣的假设，但我的近期目标是获得额外的病毒学、分子进化和反转录元素生物学方面的培训，这些都是 对我来说，对这些想法进行实验测试是绝对必要的。我已经组建了一支经验丰富、技能高超的导师/合作者团队，为我提供这种额外的培训。在为期两年的指导阶段，我将跟随迈克尔·爱默曼博士学习病毒学。我的导师哈米特·马利克博士将提供重复元素计算分析方面的额外培训，约翰·莫兰博士将就我研究逆转录元素的新试剂和技术的开发提供合作和培训。未来的培训，再加上我的研究生和博士后经验，将使我能够从多方面了解逆行元素及其宿主的生物学和进化。这些实验还将建立这种进化可能导致人类疾病的新机制。

 DESCRIPTION (provided by applicant): Primates and their endogenous retroelements have coevolved for so long that almost half the human genome is derived from retroelements sequences. However, the replication of retroelements has the potential to inflict substantial harm by jumping into essential genes or activating the immune system to drive autoimmunity. To combat these deleterious effects on their genome, hosts have evolved a battery of restriction factors to block the replication of retroelements. Despite their importance to host fitness, I have found that many of these retroelements restriction factors have evolved rapidly during primate evolution, suggesting they have been recurrently selected for functional innovation. I hypothesize that primates and their endogenous retroelements are engaged in an `evolutionary arms race', or a recurrent cycle of evasion and restriction - retroelement adaptation to evade host restriction followed by host adaptation to restrict the newly evasive retroelement. In addition, my preliminary findings suggest that some restriction factors like APOBEC3A may also have been co- opted to restrict infectious viruses in addition to endogenous retroelements. In Aim 1, I propose to characterize the causes and consequences of the rapid evolution of the APOBEC3A and APOBEC3B restriction factors, including how these factors may be evolving to chase L1 retroelements and how co-option of APOBEC3A to restrict infectious viruses has affected its ability to restrict endogenous retroelements. In Aim 2, I propose to test the hypothesis that L1TD1 (a rapidly evolving, stem cell-specific gene that was domesticated from a portion of L1) functions as a retroelements restriction factor. In Aim 3, I propose to use evolutionary analyses, as well as engineer an in vitro evolution system to test whether variation can indeed increase retroelement replication and exert selective pressure on the host. While my past training has enabled me to generate these intriguing hypotheses, my immediate goals are to gain the additional training in virology, molecular evolution, and retroelement biology that are absolutely necessary for me to experimentally test these ideas. I have assembled an accomplished and highly skilled group of mentors/collaborators to provide me with this additional training. During the two year mentored phase, I will train with Dr. Michael Emerman to learn virology. My mentor, Dr. Harmit Malik will provide additional training in the computational analysis of repetitive elements, and Dr. John Moran will provide collaboration and training on my development of new reagents and techniques to study retroelements. This future training combined with my graduate and postdoctoral experience will enable me to pursue a multifaceted approach to understanding the biology and evolution of retroelements and their hosts. These experiments will also establish novel mechanisms by which this evolution may drive human disease.