Purging of deleterious retroviral integrations at the earliest stages of genomic invasion

在基因组入侵的最早阶段清除有害的逆转录病毒整合

• 批准号: 429450856
• 负责人: Professor Dr. Alex Greenwood, Ph.D.
• 金额: --
• 依托单位: Leibniz-Institut für Zoo- und Wildtierforschung (IZW)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/429450856?language=en
• 关键词: Purging; deleterious; retroviral; integrations; earliest

In humans, about 8% of the genome consists of endogenous retrovirus-like elements, comprising a larger proportion of the genome than the coding regions of genes. Humans are not unique in this respect as many vertebrates have equal or proportionally more viral like DNA in their genomes. Therefore, a large component of the vertebrate genome reflects the process of viral invasion whereby host and virus adapt to one another. The evolutionary dynamics of this portion of the genome differs substantially from that of gene coding regions. However, the rate of this adaptive process and the underlying mechanisms remain obscure. In most vertebrates the reason for this obscurity is that the process completed millions of years ago such that the critical adaptive changes are indistinguishable from subsequent non-adaptive mutations. For example, most endogenous retroviruses are highly degraded, particularly in the retroviral envelope gene involved in viral host cell entry. However, it is unclear how and how quickly this degradation occurs during the co-evolution of host and virus. Similarly, many endogenous retroviruses exhibit signs of recombination. However, it is unclear if these are variants that occurred after endogenization and were selected for or were early events responsible for allowing endogenization to occur. An important exception among mammals to ancient endogenization is observed in the koala (Phascolarctos cinereus) which is currently undergoing a genomic retroviral invasion by the koala retrovirus, KoRV. We have preliminary evidence from studying KoRV that suggests that the rate of retroviral adaptation to the host is very rapid and largely mediated at the earliest stages by recombination with already established endogenous retroviruses in the host genome. These elements disrupt the invading retroviruses while simultaneously remobilizing themselves leading to the proliferation of replication defective viral copies in the genome and thus taming the exogenous retroviruses. Therefore, already resident endogenous retroviruses may play a defensive role against newly invading viruses. In large populations the taming process is hard to observe directly. However, on island populations subject to founder events, the fixation of KoRVs, the purging of deleterious mutants (or retroviruses) and genetic drift can be observed at a greatly accelerated rate. Using a population genetics approach on island populations of koalas established in the early 20th century from a few individual koalas (St. Bees Island, Queensland), we will examine directly the process of recombination mediated taming of retroviruses during an ongoing genomic retroviral invasion and determine the roles of genetic drift and selection in shaping almost 10% of the vertebrate genome. We will also demonstrate that the selective force is likely KoRV driven cancer.

在人类中，约8%的基因组由内源性逆转录病毒样元件组成，其占基因组的比例大于基因的编码区。人类在这方面并不独特，因为许多脊椎动物的基因组中具有相同或成比例的病毒样DNA。因此，脊椎动物基因组的一个大组成部分反映了病毒入侵的过程，宿主和病毒相互适应。这部分基因组的进化动力学与基因编码区的进化动力学有很大不同。然而，这种适应过程的速率和潜在的机制仍然不清楚。在大多数脊椎动物中，这种模糊的原因是这个过程在数百万年前完成，因此关键的适应性变化与随后的非适应性突变无法区分。例如，大多数内源性逆转录病毒是高度降解的，特别是在参与病毒宿主细胞进入的逆转录病毒包膜基因中。然而，目前还不清楚这种降解在宿主和病毒的共同进化过程中是如何发生的，以及发生的速度有多快。类似地，许多内源性逆转录病毒表现出重组的迹象。然而，目前尚不清楚这些变体是否是在内源化后发生的变体，并且是被选择的，或者是导致内源化发生的早期事件。在哺乳动物中观察到的一个重要的例外是古代内源化的考拉（Phascolarctos cinereus），目前正在经历的基因组逆转录病毒入侵的考拉逆转录病毒，KoRV。我们从研究KoRV中获得的初步证据表明，逆转录病毒对宿主的适应速度非常快，并且在最早阶段主要通过与宿主基因组中已经建立的内源性逆转录病毒重组来介导。这些元件破坏入侵的逆转录病毒，同时使其自身再活化，导致基因组中复制缺陷病毒拷贝的增殖，从而驯服外源性逆转录病毒。因此，已经存在的内源性逆转录病毒可能对新入侵的病毒起防御作用。在大种群中，驯化过程很难直接观察到。然而，在受创始人事件影响的岛屿种群中，可以观察到KoRV的固定、有害突变体（或逆转录病毒）的清除和遗传漂变的速度大大加快。使用群体遗传学的方法，在岛上的考拉建立在世纪初，从几个单独的考拉（圣蜜蜂岛，昆士兰州），我们将直接检查重组介导的逆转录病毒驯化过程中正在进行的基因组逆转录病毒入侵，并确定遗传漂变和选择的作用，在塑造近10%的脊椎动物基因组。我们还将证明选择力可能是KoRV驱动的癌症。