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，脊椎动物基因组的很大一部分（人类基因组的8%）是由来自逆转录病毒的序列组成的。本提案的总体目标是了解包膜改变突变和重组在外源性逆转录病毒（erv）转化为内源性逆转录病毒（erv）过程中改变受体趋向性和毒力的作用，并以考拉逆转录病毒(KoRV)/长猿白血病病毒（GALV）病毒进化支为模型。这将使我们了解近10%的脊椎动物基因组是如何由感染因子形成的，使用两个病毒群，其中包含一些已知的最年轻的、未完全内源性的erv。这将需要尽可能全面地确定GALV和KoRV病毒在其潜在宿主范围内的多样性，确定涉及病毒进入（受体）和复制的功能基元的变异，并测试基于细胞培养的系统中已确定的功能差异。目的1：印度尼西亚、巴布亚新几内亚和澳大利亚的啮齿动物Melomys属是唯一发现携带GALV/KoRV样病毒的非长臂猿或考拉物种，尽管只对24种中的3种进行了测试。目的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。我们将筛选成功越过华莱士线的哺乳动物GALV和KoRV样序列。目的3：确定异源逆转录病毒表达系统中非同义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.