Causes and functional consequences of chromatin evolution

项目总结 DNA包装到染色质中介导了染色体分离、端粒保护、基因组完整性和 其他基本的、保守的细胞过程。然而，许多染色质蛋白质惊人地不保守- 结构域和残基甚至在关系密切的物种之间进化得也很快。这种自相矛盾的保守， 快速进化的染色质蛋白支持的染色质依赖功能表明，维持 基本的细胞过程需要不断的创新。这一创新的生物学意义在于 几乎没有被开发过。除了少数几个例外，我们既不了解塑造 当代染色质蛋白也不是最近适应改变的染色质依赖功能。 然而，异常的染色质包装是许多血液和肿瘤、染色体癌症的标志。 先天缺陷和衰老。我的实验室集成了进化基因组学、转基因、细胞生物学和经典 遗传学以确定推动反复DNA包装创新的进化压力和 对基本的、依赖染色质的细胞和发育过程的影响。我们利用 宿主基因组与其自私基因之间“分子军备竞赛”的经典进化框架 元素，以获得对DNA包装进化的原因和功能后果的新见解。我们 特别关注适应性进化的染色质蛋白质，这些蛋白质包装了基因贫乏、富含重复和快速的 进化中的“异染色质”DNA序列富含在端粒和性染色体上。我们 假设在异染色质中茁壮成长的自私遗传元素对抗性染色体和 端粒包装蛋白。与这一假设一致，这些异染色质蛋白含有 基因组内部冲突留下的独特DNA特征--氨基酸变化的快速积累 进化过程中的突变(即正向选择)。从经验上检验反复出现的假设 一轮又一轮的自私分子逃避和异染色质蛋白抑制驱动着这些适应的信号， 我们设计了当代果蝇和黑腹果蝇自私成分之间的“进化错配” 快速进化的宿主蛋白的“复活”版本。具体地说，我们利用CRISPR/Cas9中介的编辑 删除或替换祖先重建的宿主基因。我们的初步结果显示，“男性-- 适应的“端粒蛋白去抑制端粒嵌入的自私成分。同样，删除年轻的，睾丸- 限制性异染色质蛋白释放出破坏Y染色体的自私X染色体 变速箱。我们的“反向进化遗传学”方法为我们提供了独特的机会来(1)识别 自私因素及其目标；(2)阐明自私因素获得目标的机制。 传递优势以及染色质蛋白通过什么抑制它们。通过确定生物原因 和异染色质蛋白创新的后果，我们的研究计划为 快速进化使我们的基因组容易受到染色质介导的疾病和不孕不育的影响。

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.