Virus Evolution Through Horizontal Gene Transfer

通过水平基因转移的病毒进化

基本信息

  • 批准号:
    10415466
  • 负责人:
  • 金额:
    $ 0.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-08-24 至 2024-05-31
  • 项目状态:
    已结题

项目摘要

Project Summary Horizontal gene transfer (HGT) is a well characterized phenomenon driving the evolution and genetic diversity of bacteria but its underlying mechanisms and consequences in the context of viral evolution are far less well- understood. Poxviruses and other large DNA viruses encode numerous genes of clear cellular origin. I aim to investigate how they get there and evolve following their acquisition. We have demonstrated that LINE-1 (L1) retrotransposons play a key role in the transfer of cellular genes into poxvirus genomes but do not yet understand the dynamics of how this occurs without inducing catastrophic insertional mutagenesis. How newly acquired genes evolve proviral functions and avoid deletion due to functional redundancy with their cellular ancestor. The central hypothesis of this proposal is that L1 insertions into poxvirus genomes are enriched in distal regions of the genome, avoiding disruption of essential core genes, where they can evolve to benefit the virus. I will focus on two major outstanding questions emerging from this hypothesis. In Aim 1 I will characterize the interaction between virus replication and cellular L1 machinery. This will comprise spatially defining the interaction within the cytoplasm, understanding if and how L1 activity impacts viral replication, and comprehensively characterizing the frequency and distribution of L1-mediated insertions into the viral genome. To do so I will use a combination of experimental and computational techniques spanning molecular biology, biochemistry, genetics, and next-generation sequencing. In Aim 2 I will seek to elucidate the origin and evolution of poxvirus K3L, a host-derived inhibitor of the antiviral effector PKR. K3L is a structural homolog of vertebrate eIF2 that competitively inhibits PKR-induced translational shutoff. Compared to eIF2 K3L is dramatically truncated and lacks a phosphorylation site, and so cannot mediate the antiviral functions downstream of PKR. Despite this homology, computational and phylogenetic analysis suggests K3L is most closely related to the aIF2 protein of methanogenic archaea and may not have been acquired from the host cell of an ancestral poxvirus but rather from microbes occupying similar or overlapping ecological space. Since my original submission, I have generated new preliminary data that M. fervens aIF2 inhibits vertebrate PKR, giving experimental support to my computational work. I will confirm and expand on these results in mammalian cell culture, and use experimental evolution to model the adaptation of newly acquired viral genes. The recent identification of archaeal-origin genes in other DNA viruses, provides further support for my hypothesis, but K3L would be the first known example in viruses of multicellular eukaryotes. A picture is emerging of viruses as melting pots in nodes of diverse genetic exchange and my proposed studies will illuminate mechanisms of transfer and the participation of a new family of viruses in these exchanges. These studies will advance our understanding of the process of viral co-option of cellular genes as well as explore unexpected mechanisms underlying the genetic diversity of viruses and the ecological spaces they occupy.
项目摘要 水平基因转移(Horizontal gene transfer,HGT)是一种重要的生物学现象 但在病毒进化的背景下,其潜在的机制和后果远没有那么好- 明白痘病毒和其他大型DNA病毒编码许多明确的细胞起源的基因。我的目标是 调查他们是如何到达那里并在收购后发展的。我们已经证明LINE-1(L1) 逆转录转座子在将细胞基因转移到痘病毒基因组中起关键作用, 了解这是如何发生的动力学,而不诱导灾难性的插入突变。多新 获得性基因进化出前病毒功能,并避免由于其细胞内的功能冗余而导致的缺失。 祖该建议的中心假设是痘病毒基因组中的L1插入富集了 基因组的远端区域,避免破坏必要的核心基因,在那里它们可以进化以造福人类。 病毒我将集中讨论从这一假设中出现的两个主要的悬而未决的问题。目标1我会 表征病毒复制和细胞L1机制之间的相互作用。这将在空间上包括 定义细胞质内的相互作用,了解L1活性是否以及如何影响病毒复制, 全面表征L1介导的插入到病毒基因组中的频率和分布。 为了做到这一点,我将结合实验和计算技术,跨越分子生物学, 生物化学、遗传学和下一代测序。在目标2中,我将试图阐明 痘病毒K3 L的进化,一种抗病毒效应PKR的宿主衍生抑制剂。K3 L是一种结构同源物, 竞争性抑制PKR诱导的翻译关闭。与eIF 2相比, 显著截短且缺乏磷酸化位点,因此不能介导抗病毒功能 PKR下游。尽管有这种同源性,计算和系统发育分析表明K3 L是最常见的。 与产甲烷古菌的aIF 2 α蛋白密切相关,可能不是从宿主获得的 痘病毒起源于痘病毒祖先的细胞,而是来自占据相似或重叠生态空间的微生物。以来 我的原始提交,我已经产生了新的初步数据,M。fervens aIF 2 β抑制脊椎动物PKR, 为我的计算工作提供实验支持。我将确认并扩展这些结果, 哺乳动物细胞培养,并使用实验进化来模拟新获得的病毒基因的适应。 最近在其他DNA病毒中发现的古细菌起源基因,为我的研究提供了进一步的支持。 假设,但K3 L将是第一个已知的例子,在病毒的多细胞真核生物。一图 病毒作为不同基因交换节点的大熔炉的出现,我提出的研究将 阐明了转移机制和一个新的病毒家族参与这些交换。这些 这些研究将促进我们对细胞基因的病毒共选择过程的理解,并探索 病毒遗传多样性及其所占据的生态空间的潜在机制。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Stephen Goldstein其他文献

Stephen Goldstein的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Stephen Goldstein', 18)}}的其他基金

Virus Evolution Through Horizontal Gene Transfer
通过水平基因转移的病毒进化
  • 批准号:
    10157165
  • 财政年份:
    2021
  • 资助金额:
    $ 0.25万
  • 项目类别:
Virus Evolution Through Horizontal Gene Transfer
通过水平基因转移的病毒进化
  • 批准号:
    10403422
  • 财政年份:
    2021
  • 资助金额:
    $ 0.25万
  • 项目类别:
Virus Evolution Through Horizontal Gene Transfer
通过水平基因转移的病毒进化
  • 批准号:
    10640106
  • 财政年份:
    2021
  • 资助金额:
    $ 0.25万
  • 项目类别:
Investigating MERS-CoV NS4b as a modulator of the host antiviral response in the nucleus
研究 MERS-CoV NS4b 作为细胞核内宿主抗病毒反应的调节剂
  • 批准号:
    9619001
  • 财政年份:
    2017
  • 资助金额:
    $ 0.25万
  • 项目类别:

相似海外基金

The mobilome of the anaerobic methanotrophic archaea Methanoperedenaceae
厌氧甲烷氧化古菌 Methanoperedenaceae 的移动组
  • 批准号:
    DP240100992
  • 财政年份:
    2024
  • 资助金额:
    $ 0.25万
  • 项目类别:
    Discovery Projects
Harnessing the potential of Archaea - Training Europe's next visionaries for an innovative and sustainable future
利用古生菌的潜力 - 培训欧洲的下一代有远见的人以实现创新和可持续的未来
  • 批准号:
    EP/Y031407/1
  • 财政年份:
    2024
  • 资助金额:
    $ 0.25万
  • 项目类别:
    Research Grant
Asgard archaea: the first eukaryotic cells?
阿斯加德古菌:第一个真核细胞?
  • 批准号:
    DP230100769
  • 财政年份:
    2023
  • 资助金额:
    $ 0.25万
  • 项目类别:
    Discovery Projects
Probing the mechanisms that couple genome segregation to chromosome organization in Archaea
探讨古细菌基因组分离与染色体组织的耦合机制
  • 批准号:
    BB/X00645X/1
  • 财政年份:
    2023
  • 资助金额:
    $ 0.25万
  • 项目类别:
    Research Grant
Probing the mechanisms that couple genome segregation to chromosome organisation in Archaea
探讨古细菌基因组分离与染色体组织的耦合机制
  • 批准号:
    BB/X006506/1
  • 财政年份:
    2023
  • 资助金额:
    $ 0.25万
  • 项目类别:
    Research Grant
Functional and structural analysis of proline dehydrogenase for elucidation of proline biosynthesis in hyperthermophilic archaea
脯氨酸脱氢酶的功能和结构分析,用于阐明超嗜热古菌中脯氨酸的生物合成
  • 批准号:
    23K05658
  • 财政年份:
    2023
  • 资助金额:
    $ 0.25万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Enigmatic archaea in subsurface environments
地下环境中神秘的古细菌
  • 批准号:
    23H00387
  • 财政年份:
    2023
  • 资助金额:
    $ 0.25万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Development of novel denitrification process by methanotrophic archaea in bioelectroche mical system
生物电化学系统中甲烷氧化古菌新型反硝化工艺的发展
  • 批准号:
    22KF0377
  • 财政年份:
    2023
  • 资助金额:
    $ 0.25万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Conference: 2023 Archaea: Ecology, Metabolism and Molecular Biology GRC and GRS The Root and Branch of Discovery: Lessons on Life from the Archaea
会议:2023 古细菌:生态学、代谢和分子生物学 GRC 和 GRS 发现的根源和分支:古细菌的生命教训
  • 批准号:
    2324896
  • 财政年份:
    2023
  • 资助金额:
    $ 0.25万
  • 项目类别:
    Standard Grant
Elucidation of biological and metabolic diversity of methanogenic archaea and reconstruction of subsurface carbon cycle
阐明产甲烷古菌的生物和代谢多样性以及重建地下碳循环
  • 批准号:
    23H03534
  • 财政年份:
    2023
  • 资助金额:
    $ 0.25万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了