Mechanisms and Evolution of Host Tolerance to Transposable Elements

项目总结/摘要 转座因子（Transposable elements，TE）是一种普遍存在的基因组寄生物，占细胞核DNA的70%以上。 某些血统的DNA。除了产生有害突变外，TE还可以产生致命的遗传毒性效应 通过在插入和切除过程中引起双链断裂而对宿主细胞产生影响。宿主基因组有两个 避免寄生性TE的适应性成本的机制：抗性和耐受性。机制 抗性通过抑制转座降低TE负荷，而耐受机制降低适合度 现有技术的后果。虽然对TE的抗性被广泛研究，特别是小RNA 宽容作为一种分类学上普遍存在的策略，是我最近提出的一个新概念。 此外，通过一个创新的QTL定位实验，我提供了关键的原则证明，宽容 果蝇的遗传变异在未来，我建议在这些最新发现的基础上， 扩大我们对耐受机制和进化的理解。 首先，我们将研究布鲁诺依赖性耐受P- 元件DNA转座子布鲁诺是卵子发生的发育调节器， 证明是雌性生殖系耐受不受调节的P元件转座的主要决定因素。通过 结合突变等位基因的遗传分析，以及我们从自然界中分离出的耐受性良好的布鲁诺变体， 人群，我们将揭示布鲁诺依赖性耐受的潜在机制。此外，通过采取 利用历史悠久的D.我们将评估黑腹动物的 20世纪世纪中期，耐布鲁诺变种对宿主适应P-元素入侵的贡献。 我的第二个研究方向的动机是我们发现异染色质的自然变异是 细胞如何受到不受调节的转座影响的一个重要决定因素： 异染色质和减少的异染色质形成降低细胞耐受性。这些观察结果 这让人想起芭芭拉·麦克林托克的“基因组休克”模型，在该模型中，DNA损伤或 细胞压力触发释放通常静止重复。因此我提议调查 异染色质变异与细胞和调控水平上对遗传毒性应激的反应之间的关系。 我的长期目标是揭示TE和他们的宿主之间复杂而亲密的关系， 有助于基因组进化和形成配子发生的进化。更好地了解这些 相互作用是至关重要的，因为：1）它们是TE和宿主细胞共同进化的界面，2） TE活性与许多肿瘤类型和年龄相关的神经退行性疾病的发病、进展有关。 3）宿主基因组之间TE含量和分布的巨大差异在很大程度上仍然存在 无法解释

PROJECT SUMMARY/ABSTRACT Transposable elements (TEs) are omnipresent genomic parasites, comprising >70% of the nuclear DNA in certain lineages. In addition to producing deleterious mutations, TEs can exert lethal, genotoxic effects on host cells by causing double-stranded breaks during insertion and excision. Host genomes have two mechanisms for avoiding the fitness costs of parasitic TEs: resistance and tolerance. Mechanisms of resistance reduce TE load by repressing transposition, while mechanisms of tolerance reduce the fitness consequences of existing TEs. While resistance to TEs is studied extensively, with small-RNAs in particular emerging as a taxonomically widespread strategy, tolerance is a new concept that I have recently proposed. Furthermore, through an innovative QTL mapping experiment, I provided critical proof-of-principle for tolerant genetic variants in Drosophila melanogaster. In the future, I propose to build on these recent discoveries to expand our understanding of tolerance mechanisms and evolution. First, we will study the mechanism and recent evolutionary history of bruno-dependent tolerance to P- element DNA transposons. Bruno is a developmental regulator of oogenesis, which we have recently demonstrated is a major determinant of female germline tolerance to unregulated P-element transposition. By combining genetic analysis of mutant alleles, as well tolerant bruno variants we have isolated from natural populations, we will reveal the underlying mechanism of bruno-dependent tolerance. Furthermore, by taking advantage of the unique opportunity provided by historic D. melanogaster collections, we will evaluate the contribution of bruno tolerant variants to the host adaptation to the P-element invasion in the mid 20th century. My second research direction is motivated by our discovery that natural variation in heterochromatin is an important determinant of how cells are impacted by unregulated transposition: larger doses of heterochromatin and reduced heterochromatin formation decrease cellular tolerance. These observations are reminiscent of Barbara McClintock's “genomic shock” model, in which tremors arising from DNA damage or cellular stress trigger the release normally quiescent repeats. I therefore propose to interrogate the relationship between heterochromatic variation and response to genotoxic stress at both the cellular and regulatory levels. My long-term goal is to reveal complex and intimate relationships between TEs and their hosts, which contribute to genome evolution and shape the evolution of gametogenesis. A better understanding of these interactions is of vital importance because: 1) they are the interface at which TEs and host cells coevolve, 2) TE activity is implicated in the onset, progression of many tumor types and age related neurodegenerative diseases, and 3) vast differences in TE content and distribution between host genomes remain largely unexplained.