Genome invasion: understanding the evolutionary and functional roles of mutation and recombination at the earliest stages of retroviral endogenization

脊椎动物基因组通常被认为是由基因和非编码序列组成的，这些基因和非编码序列要么在各种形式的自然选择下进化，要么是中性进化。然而，在这方面，脊椎动物基因组的一个非常大的组成部分本提案的总体目标是了解在使用考拉逆转录病毒（KoRV）/巨猿白血病病毒（GALV）将外源性逆转录病毒转化为内源性逆转录病毒（ERV）期间，改变包膜的突变和重组在改变受体嗜性和毒力方面的作用。病毒进化枝作为模型。这将使我们能够了解近10%的脊椎动物基因组是如何由感染因子形成的，使用两个病毒组，其中包含一些已知的最年轻的和不完全内源化的ERV。这将需要尽可能全面地鉴定GALV和KoRV病毒在其潜在宿主范围内的多样性，鉴定参与病毒进入的功能基序的变异，（受体）和复制以及测试在基于细胞培养的系统中鉴定了功能上的差异。印度尼西亚、巴布亚新几内亚和澳大利亚的Melomys属啮齿动物是唯一被发现携带GALV/KoRV样病毒的非长颈鹿或考拉物种，尽管24个物种中只有3个被测试过将对该属进行KoRV和GALV的全面筛查。目标2：华莱士线是东南亚与印度尼西亚，巴布亚新几内亚和澳大利亚大部分地区之间的地理屏障。目的3：在异源逆转录病毒表达系统中，鉴定非同义GAG和ENV差异的功能意义。

Vertebrate genomes are generally considered to be composed of genes and non-coding sequences that are either evolving under various forms of natural selection or are evolving neutrally. However, a very large component of the vertebrate genome (8% in humans) is composed of sequences deriving from retroviruses The overall objective of this proposal is to understand the role envelope altering mutations and recombination play in altering receptor tropism and virulence during the conversion of exogenous retroviruses to endogenous retroviruses (ERVs) using the Koala retrovirus (KoRV)/gibbon ape leukemia virus (GALV) viral clade as a model. This will allow us to understand how almost 10% of vertebrate genomes have been formed by infectious agents, using two viral groups containing some of the youngest known and not fully endogenized ERVs. This will entail identifying, as comprehensively as possible, GALV and KoRV virus diversity across their potential host range, identifying variation in functional motifs involved in viral entry (receptor) and replication and testing identified differences functionally in cell culture based systems.Objective 1: The rodent genus Melomys of Indonesia, Papua New Guinea and Australia are the only non gibbon or Koala species found to carry GALV/KoRV like viruses, though only 3 of 24 species have been tested. The genus will be fully screened for KoRV and GALV. Objective 2: The Wallace Line is a geographical barrier between Southeast Asia and much of Indonesia, Papau New Guinea and Australia. We will screen mammals that have successfully crossed the Wallace Line for GALV and KoRV like sequencesObjective 3: Identify functional significance of non-synonymous GAG and ENV differences in a heterologous retroviral expression system.