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

在人类中，约8%的基因组由内源性逆转录病毒样元件组成，占基因组的比例高于基因编码区。在这方面，人类并不是独一无二的，因为许多脊椎动物的基因组中有相同或比例更像DNA的病毒。因此，脊椎动物基因组的很大一部分反映了病毒入侵的过程，宿主和病毒通过这种过程相互适应。基因组这一部分的进化动态与基因编码区的进化动态有很大不同。然而，这种适应过程的速度和潜在的机制仍然不清楚。在大多数脊椎动物中，这种默默无闻的原因是这个过程在数百万年前就完成了，以至于关键的适应性变化与随后的非适应性突变难以区分。例如，大多数内源性逆转录病毒都是高度降解的，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，目前尚不清楚在宿主和病毒的共同进化过程中，这种降解发生的方式和速度有多快。同样，许多内源性逆转录病毒也显示出重组的迹象。然而，目前尚不清楚这些变异体是否是发生在内源性之后的变异体，或者是导致内源性发生的早期事件。在哺乳动物中，一个重要的例外是考拉(Phascolarctos Cinereus)，它目前正在接受考拉逆转录病毒KoRV的基因组逆转录病毒入侵。我们从对KoRV的研究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，并且在最早的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的重组来调节。这些元件破坏入侵的逆转录病毒，同时重新动员自己，导致基因组中复制缺陷的病毒拷贝的增殖，从而驯服外源逆转录病毒。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到防御作用。在大量种群中，驯化过程很难直接观察到。然而，在受到创始人事件影响的岛屿种群中，可以极大地加速观察到KoRV的固定、有害突变(或逆转录病毒)的清除和遗传漂移。利用种群遗传学方法对20世纪初从几只考拉个体(昆士兰圣蜜蜂岛)建立的考拉岛屿种群，我们将直接研究正在进行的基因组逆转录病毒入侵期间重组介导的逆转录病毒驯化过程，并确定遗传漂移和选择在塑造脊椎动物基因组近10%的过程中所起的作用。我们还将证明这种选择性力量可能是由KoRV驱动的癌症。

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.