Phylogenomics and functional diversification of the Heterochromatin Protein 1 gen

描述（由申请人提供）：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。这些过程在动物王国中是严格保守的，然而大量的自私转座元件、卫星重复和分离扭曲的位点使得这个基因组区室在进化过程中具有高度的动态性。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，并且通常在严格的约束下进化。然而，我们最近对果蝇基因组中HP1注释的手工计算方法将这个家族从3个基因扩展到14个基因，其中大多数基因进化得很快。这种动态进化暗示了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通过小RNA途径调节雌性种系对转座因子的防御。我建议完成我们在12个测序的果蝇物种中所有hp1样基因的彻底搜索，然后在细胞培养和体内确认组织面板上的转录和荧光标记蛋白的异染色质定位。通过群体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元素的分子军备竞赛相一致。同时，我将验证通过piRNA途径的转座因子防御驱动HP1D/rhino及其假定的雄性类似物HP1E的快速进化的具体假设。最后，我将把我对HP1注释和验证的综合方法应用于包括人类在内的高等灵长类动物。目前人类基因组中只有三个hp1样基因被注释，这些基因在十多年前被描述为与最初的三个果蝇hp1样基因同源。与果蝇类似，这三种人类hp1在严格的约束下进化。我对人类基因组中许多未表征的HP1衍生基因复制事件的初步调查表明，尽管未被探索，但与果蝇外参与遗传冲突的新型HP1样基因的进化动力学是一致的。

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.