Causes and functional consequences of chromatin evolution

项目摘要 DNA包装到染色质中介导染色体分离，端粒保护，基因组完整性， 其他重要的、保守的细胞过程。然而，许多染色质蛋白是惊人的不保守- 结构域和残基甚至在密切相关的物种之间迅速进化。这种保守的悖论， 由快速进化的染色质蛋白支持的染色质依赖性功能表明， 基本的细胞过程需要不断的创新。这项创新的生物学意义是 几乎未被探索过除了少数例外，我们既不了解塑造人类的进化力量 当代染色质蛋白质，也没有染色质依赖的功能修改最近的适应。 然而，异常的染色质包装是许多血液和肿瘤癌症的标志，染色体异常是癌症的标志。 出生缺陷和衰老我的实验室整合了进化基因组学、转基因学、细胞生物学和经典 遗传学，以确定推动经常性DNA包装创新的进化压力， 基本的，染色质依赖的细胞和发育过程的后果。我们利用 这是一个经典的进化框架，即宿主基因组与其自私的基因组之间的“分子军备竞赛”。 元素，以获得新的见解的原因和功能后果的DNA包装进化。我们 专注于适应性进化的染色质蛋白，包装基因贫乏，重复丰富，快速- 进化的“异染色质”DNA序列在端粒和沿着性染色体富集。我们 假设在异染色质中茁壮成长的自私的遗传因素，对抗性染色体， 端粒包装蛋白。与这一假设相一致，这些异染色质蛋白含有 基因组内冲突留下的独特DNA特征-氨基酸变化的快速积累 在进化时间上的突变（即，积极选择）。为了实证检验复发性 自私元件逃避和异染色质蛋白抑制的发作驱动这些适应的特征， 我们设计了当代果蝇自私元素之间的“进化失配”， 快速进化的宿主蛋白质的“复活”版本。具体来说，我们利用CRISPR/Cas9介导的编辑 删除或交换祖先重建的宿主基因。我们的初步研究结果表明，“马尔- 适应性”端粒蛋白去抑制嵌入端粒的自私元件。同样，删除年轻的睾丸- 限制性异染色质蛋白释放出自私的X染色体，破坏Y染色体 传输我们的“反向进化遗传学”方法为我们提供了独特的机会，（1）识别 自私元素及其靶点;（2）阐明自私元素获得 传递的优势，并通过染色质蛋白抑制它们。通过确定生物学原因 和异染色质蛋白质创新的后果，我们的研究计划提供了新的见解， 快速的进化使我们的基因组容易受到染色质介导的疾病和不育的影响。

PROJECT SUMMARY DNA packaging into chromatin mediates chromosome segregation, telomere protection, genome integrity, and other essential, conserved cellular processes. However, many chromatin proteins are strikingly unconserved— domains and residues evolve rapidly between even closely related species. This paradox of conserved, chromatin-dependent functions supported by fast-evolving chromatin proteins suggests that maintaining essential cellular processes requires recurrent innovation. The biological significance of this innovation is virtually unexplored. With few exceptions, we understand neither the evolutionary forces that shape contemporary chromatin proteins nor the chromatin-dependent functions modified by recent adaptation. Nevertheless, aberrant chromatin packaging is the hallmark of many blood and tumor cancers, chromosomal birth defects, and aging. My lab integrates evolutionary genomics, transgenics, cell biology, and classical genetics to identify the evolutionary pressures that drive recurrent DNA packaging innovation and the consequences for fundamental, chromatin-dependent cellular and developmental processes. We utilize the classic evolutionary framework of a “molecular arms race” between a host genome and its selfish genetic elements to gain new insights into the causes and functional consequences of DNA packaging evolution. We focus specifically on adaptively evolving chromatin proteins that package the gene-poor, repeat-rich, and fast- evolving “heterochromatic” DNA sequence enriched at telomeres and along the sex chromosomes. We hypothesize that selfish genetic elements, which thrive in heterochromatin, antagonize sex chromosome and telomere packaging proteins. Consistent with this hypothesis, these heterochromatin proteins harbor the distinct DNA signature left behind by intra-genomic conflict—the rapid accumulation of amino acid-changing mutations over evolutionary time (i.e., positive selection). To empirically test the hypothesis that recurrent bouts of selfish element evasion and heterochromatin protein suppression drive these signatures of adaptation, we engineer “evolutionary mismatches” between contemporary Drosophila melanogaster selfish elements and “resurrected” versions of fast-evolving host proteins. Specifically, we leverage CRISPR/Cas9-mediated editing to delete or to swap in an ancestrally reconstructed host gene. Our preliminary results indicate that “mal- adapted” telomere proteins de-repress telomere-embedded selfish elements. Similarly, deleting young, testis- restricted heterochromatin proteins unleashes a selfish X chromosome that sabotages Y chromosome transmission. Our “reverse evolutionary genetics” approach offers us the unique opportunity to (1) identify selfish elements and their targets and (2) elucidate the mechanisms by which selfish elements gain a transmission advantage and by which chromatin proteins suppress them. By identifying the biological causes and consequences of heterochromatin protein innovation, our research program provides new insights into how rapid evolution renders our genome vulnerable to chromatin-mediated disease and infertility.