Phylogenomics and functional diversification of the Heterochromatin Protein 1 gen

描述(申请人提供)：异染色质是我们基因组中缺乏基因、富含卫星、转录沉默的区域，它支持染色体分离和端粒完整性等基本细胞过程。这些过程在整个动物界都是严格保守的，然而丰富的自私转座元件、卫星重复和扭曲分离的基因座使这个基因组舱随着进化时间的推移而高度动态。异染色质蛋白1(HP1)基因家族的三个创始成员支持这些保守的过程，通常在严格的约束下进化。然而，我们最近手工策划的跨果蝇基因组HP1注释的计算方法，将这个家族从3个基因扩大到14个基因，其中大多数进化得很快。这种动态进化意味着异染色质丰富的自私基因组寄生虫和这些异染色质相关宿主蛋白之间的分子军备竞赛。例如，HP1D/Rhino通过一条小RNA途径调节雌性生殖系对转座子的防御。我建议完成我们对12个已测序果蝇物种中所有HP1样基因的详尽搜索，然后确认在细胞培养和体内荧光标记蛋白的转录和异染色质定位。使用种群遗传和分子进化分析，我将严格确定序列进化模式是否与正在进行的带有自私遗传因素的分子军备竞赛一致。同时，我将测试特定的假设，即通过piRNA途径的转座元件防御驱动HP1D/犀牛及其推定的男性类似物HP1E的快速进化。最后，我将把我的全面方法应用于HP1的注释和验证，包括人类在内的高等灵长类动物。目前在人类基因组中只有三个类HP1基因被注释，十多年前通过与最初的三个果蝇类HP1基因的同源性来描述。这三个人类HP1基因让人联想到果蝇，它们是在严格的限制下进化的。我对人类基因组中许多未刻画的HP1衍生基因复制事件的初步调查表明，尽管未被探索，但类似的进化动力学与新的HP1样基因在果蝇以外参与遗传冲突是一致的。 公共卫生相关性：目前在人类基因组中注释的所有三种异染色质蛋白1(HP1)基因都与至少一种组织类型/细胞系的癌症进展有关，包括乳腺癌、脑、结肠和卵巢，以及白血病和乳头状甲状腺癌。我的进化/比较基因组学方法有望确定HP1基因的新生物学功能，从而促进我们对癌细胞中基因调控和染色体分离缺陷的理解。

DESCRIPTION (provided by applicant): Heterochromatin is the gene-poor, satellite-rich, transcriptionally silent compartment of our genome that supports such basic cellular processes as chromosome segregation and telomere integrity. These processes are strictly conserved across the animal kingdom, yet abundant selfish transposable elements, satellite repeats, and segregation- distorting loci render this genome compartment highly dynamic over evolutionary time. The three founding members of the Heterochromatin Protein 1(HP1) gene family support these conserved processes and generally evolve under strict constraint. Our recent hand-curated computational approach to HP1 annotation across Drosophila genomes, however, expanded this family from three to 14 genes, most of which evolve rapidly. This dynamic evolution implicates a molecular arms race between heterochromatin's abundant selfish genomic parasites and these heterochromatin-associated host proteins. HP1D/Rhino, for example, regulates female germline defense against transposable elements via a small RNA pathway. I propose to complete our exhaustive search for all HP1-like genes in the 12 sequenced Drosophila species followed by confirmation of both transcription across a tissue panel and heterochromatin localization of fluorescently tagged proteins in cell culture and in vivo. Using population genetic and molecular evolution analyses, I will rigorously determine if patterns of sequence evolution are consistent with an ongoing molecular arms race with selfish genetic elements. In parallel, I will test the specific hypothesis that transposable element defense via the piRNA pathway drives the rapid evolution of HP1D/rhino and its putative male analog, HP1E. Finally, I will apply my comprehensive approach to HP1 annotation and verification to higher primates, including humans. Only three HP1-like genes are currently annotated in the human genome, described over a decade ago by homology to the original three Drosophila HP1-like genes. Reminiscent of Drosophila, these three human HP1s are evolving under strict constraint. My preliminary survey of the many uncharacterized HP1-derived gene duplication events across the human genome implicates similar, though unexplored, evolutionary dynamics consistent with novel HP1- like genes engaged in genetic conflict outside of Drosophila. PUBLIC HEALTH RELEVANCE: All three Heterochromatin Protein 1 (HP1) genes currently annotated in the human genome are linked to cancer progression in at least one tissue type/cell line, including breast, brain, colon, and ovary, and in leukemia and papillary thyroid carcinoma. My evolutionary/comparative genomic approach promises to identify new biological functions for HP1 genes that advance our understanding of the gene regulation and chromosome segregation defects in cancer cells.