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

在人类中，大约8%的基因组由内源性逆转录病毒样元素组成，其在基因组中的比例大于基因编码区。人类在这方面并不是唯一的，因为许多脊椎动物的基因组中都有相同或比例更多的病毒样DNA。因此，脊椎动物基因组的很大一部分反映了宿主和病毒相互适应的病毒入侵过程。这部分基因组的进化动态与基因编码区有很大的不同。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就完成了，因此关键的适应性变化与随后的非适应性突变是无法区分的。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，在宿主和病毒的共同进化过程中，这种降解如何以及多快发生尚不清楚。同样，许多内源性逆转录病毒也表现出重组的迹象。然而，目前尚不清楚这些变异是在内源性作用发生后被选择的，还是导致内源性作用发生的早期事件。在哺乳动物中，一个重要的例外是考拉（Phascolarctos cinereus），它目前正在经历考拉逆转录病毒KoRV的基因组逆转录病毒入侵。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是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的。这些元件破坏入侵的逆转录病毒，同时重新激活自身，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，在受创始者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。利用种群遗传学方法对20世纪初建立的考拉岛屿种群进行研究，研究对象是一些考拉个体（昆士兰圣蜂岛），我们将直接研究逆转录病毒入侵过程中重组介导的逆转录病毒驯服过程，并确定遗传drift和遗传选择在形成近10%的脊椎动物基因组中的作用。我们还将证明这种选择力很可能是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.