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，要么在中性进化。然而，脊椎动物基因组的很大一部分(在人类中占8%)是由来自逆转录病毒的序列组成的。本研究的总体目标是以考拉逆转录病毒(KoRV)/长臂猿白血病病毒(GalV)病毒分支为模型，了解外源逆转录病毒向内源性逆转录病毒(ERV)转化过程中，包膜改变突变和重组在改变受体趋向性和毒力方面所起的作用。这将使我们了解近10%的脊椎动物基因组是如何由感染性病原体形成的，使用两个病毒组，其中包含一些最年轻的已知和未完全内源性的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，鉴定病毒进入(受体)所涉及的功能基序的变异，并在基于细胞培养的系统中复制和测试确定功能差异。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属Melomys是唯一发现携带Galv/KoRV样病毒的非长臂猿或考拉物种，尽管24种中只有3种已被检测。该属将对KoRV和Galv进行全面筛查。目标2：华莱士线是东南亚与印度尼西亚大部分地区、巴布亚、新几内亚和澳大利亚之间的地理屏障。我们将筛选成功跨越Wallace线的哺乳动物的Galv和KoRV样序列目标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.